Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same

ABSTRACT

Provided herein are compositions that contain water-soluble vitamin E derivative mixtures (compositions), such as tocopheryl polyethylene glycol succinate (TPGS), TPGS analogs, TPGS homologs and TPGS derivatives. The water-soluble vitamin E mixtures contain mixtures of dimers and monomers of the vitamin E derivative. Provided are products containing the water-soluble vitamin E derivative mixtures, including capsules, soft gel compositions, pre-gel compositions, emulsions and powders.

RELATED APPLICATIONS

This application is a divisional of co-pending U.S. patent applicationSer. No. 14/866,808, now allowed, entitled “FORMULATIONS OFWATER-SOLUBLE DERIVATIVES OF VITAMIN E AND SOFT GEL COMPOSITIONS,CONCENTRATES AND POWDERS CONTAINING THE SAME,” filed Sep. 25, 2015, toPhilip J. Bromley.

U.S. patent application Ser. No. 14/866,808 is a continuation ofPCT/US2015/051097, filed Sep. 18, 2015, entitled “PRE-SPRAY EMULSIONSAND POWDERS CONTAINING NON-POLAR COMPOUNDS,” which claims priority under35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/052,433, filedSep. 18, 2014, entitled “PRE-SPRAY EMULSIONS AND POWDERS CONTAININGNON-POLAR COMPOUNDS,” and to U.S. Provisional Application No.62/052,450, filed Sep. 18, 2014, entitled “FORMULATIONS OF WATER-SOLUBLEDERIVATIVES OF VITAMIN E AND SOFT GEL COMPOSITIONS, CONCENTRATES ANDPOWDERS CONTAINING SAME,” each to Philip J. Bromley.

U.S. patent application Ser. No. 14/866,808 also is a continuation ofPCT/US2015/051083, filed Sep. 18, 2015, entitled “SOFT GEL COMPOSITIONSAND PRE-GEL CONCENTRATES,” which also claims priority to U.S.Provisional Application No. 62/052,435, filed Sep. 18, 2014, entitled“SOFT GEL COMPOSITIONS AND PRE-GEL CONCENTRATES,” and to U.S.Provisional Application No. 62/052,450, filed Sep. 18, 2014, entitled“FORMULATIONS OF WATER-SOLUBLE DERIVATIVES OF VITAMIN E AND SOFT GELCOMPOSITIONS, CONCENTRATES AND POWDERS CONTAINING SAME,” each to PhilipJ. Bromley.

This application is related to co-pending U.S. application Ser. No.14/866,717, filed Sep. 25, 2015, entitled “PRE-SPRAY EMULSIONS ANDPOWDERS CONTAINING NON-POLAR COMPOUNDS,” to Philip J. Bromley. U.S.application Ser. No. 14/866,717 also claims priority to U.S. ProvisionalApplication No. 62/052,433, filed Sep. 18, 2014, entitled “PRE-SPRAYEMULSIONS AND POWDERS CONTAINING NON-POLAR COMPOUNDS,” and to U.S.Provisional Application No. 62/052,450, filed Sep. 18, 2014, entitled“FORMULATIONS OF WATER-SOLUBLE DERIVATIVES OF VITAMIN E AND SOFT GELCOMPOSITIONS, CONCENTRATES AND POWDERS CONTAINING SAME,” each to PhilipJ. Bromley.

This application also is related to U.S. application Ser. No.14/866,724, filed Sep. 25, 2015, now abandoned, entitled “SOFT GELCOMPOSITIONS AND PRE-GEL CONCENTRATES,” to Philip J. Bromley. U.S.application Ser. No. 14/866,724 is a continuation of PCT/US2015/051083,filed Sep. 18, 2015, entitled “SOFT GEL COMPOSITIONS AND PRE-GELCONCENTRATES,” which also claims priority to U.S. ProvisionalApplication Ser. No. 62/052,435, filed Sep. 18, 2014, entitled “SOFT GELCOMPOSITIONS AND PRE-GEL CONCENTRATES,” and to U.S. ProvisionalApplication Ser. No. 62/052,450, filed Sep. 18, 2014, entitled“FORMULATIONS OF WATER-SOLUBLE DERIVATIVES OF VITAMIN E AND SOFT GELCOMPOSITIONS, CONCENTRATES AND POWDERS CONTAINING SAME,” each to PhilipJ. Bromley.

This application also is related to U.S. patent application Ser. No.14/207,310, filed Mar. 12, 2014, now U.S. Pat. No. 9,351,517, issued onMay 31, 2016, entitled “FORMULATIONS OF WATER-SOLUBLE DERIVATIVES OFVITAMIN E AND COMPOSITIONS CONTAINING SAME,” which claims priority toU.S. Provisional Application No. 61/852,243, filed Mar. 15, 2013,entitled “FORMULATIONS OF PEG-DERIVATIVES OF VITAMIN E AND COMPOSITIONSCONTAINING SAME,” and International PCT Application No.PCT/US2014/025006, filed Mar. 12, 2014, published as WO 2014/151109 onSep. 25, 2014, entitled “FORMULATIONS OF WATER-SOLUBLE DERIVATIVES OFVITAMIN E AND COMPOSITIONS CONTAINING SAME,” which also claims priorityto U.S. Provisional Application No. 61/852,243, filed Mar. 15, 2013,entitled “FORMULATIONS OF PEG-DERIVATIVES OF VITAMIN E AND COMPOSITIONSCONTAINING SAME” and to U.S. Provisional Application No. 61/863,732,filed Aug. 8, 2013, entitled “FORMULATIONS OF WATER-SOLUBLE DERIVATIVESOF VITAMIN E AND COMPOSITIONS CONTAINING SAME,” each to Philip J.Bromley.

The subject matter of each of the above-referenced applications isincorporated by reference in its entirety.

FIELD OF THE INVENTION

Provided herein are compositions that contain water-soluble vitamin Ederivative mixtures (compositions), such as tocopheryl polyethyleneglycol succinate (TPGS), TPGS analogs, TPGS homologs and TPGSderivatives. The water-soluble vitamin E mixtures contain mixtures ofdimers and monomers of the vitamin E derivative. Also provided areproducts containing the water-soluble vitamin E derivative mixtures,including soft gel compositions, pre-gel concentrates, capsules and softgels compositions that contain the pre-gel concentrates, and powders,and methods for preparing the products. Methods for preparing theproducts are provided.

BACKGROUND

Non-polar ingredients and compounds are not easily dissolved in aqueoussolutions, such as water or other polar solvents. A number of non-polaringredients and compounds are used in compositions for human ingestion.These include, for example, pharmaceuticals, nutraceuticals and/ordietary supplements. Exemplary of non-polar ingredients are vitamins andminerals, fatty acids, and other non-polar compounds, non-polarbioactive agents and non-polar ingredients. Because of poor watersolubility, inclusion of non-polar ingredients and compounds in productsfor human consumption, for example, in supplements, foods and beverages,can be problematic, and the amount of non-polar ingredient that can beincluded is limited.

Water-soluble forms of vitamin E, such as TPGS (D-α-tocopherylpolyethylene glycol succinate), in particular TPGS 1000 (D-α-tocopherylpolyethylene glycol 1000 succinate), have been approved by the FDA asvitamin E nutritional supplements. TPGS is a stable, tasteless andodorless source of readily bioavailable vitamin E that does nothydrolyze under normal conditions. TPGS, TPGS homologs, TPGS analogs andTPGS derivatives also are used as surfactants, and have been used toprepare stabilized formulations of food, beverage, pharmaceutical ornutraceutical products containing non-polar compounds. TPGS (andhomologs, analogs and derivatives) has been used as a solubilizing agentfor such stabilized formulations, such as water-soluble formulationsthat contain water-insoluble non-polar compounds, such as drugs,vitamins, or other biologically active compounds, such as natural andnon-natural omega-fatty acids. Thus, TPGS possesses the dual function ofproviding additional dietary vitamin E and providing stabilization to aformulation.

Available products containing non-polar compounds, particularly productsfor human consumption, such as food and beverage products containingnon-polar compounds, and methods for formulating such products, arelimited. In addition, the amount, or concentration, of non-polarcompounds in available food and beverage products is limited due to thedisplay of undesirable organoleptic properties when the amount ofnon-polar compound is increased. Thus, there is a need to developproducts for human consumption, such as food and beverage products, thatcontain non-polar compounds and methods for making the products. Thereis an additional need to develop products for human consumption, such asfood and beverage products, that contain a higher amount of non-polarcompound than is offered in available food and beverage products. Therealso is a need to develop products for human consumption, such as foodand beverage products, that retain their organoleptic properties whenthey contain a higher amount of non-polar compound. Accordingly, it isamong the objects herein to provide food and beverage productscontaining non-polar compounds, in particular, food and beverageproducts containing more non-polar compounds than available productsthat retain desirable organoleptic properties, and methods for makingthe products.

SUMMARY

Provided herein are compositions that contain water-soluble vitamin Ederivative mixtures (compositions) and a non-polar ingredient andoptionally, additional ingredients. The water-soluble vitamin Ederivative mixtures (compositions) contain a relatively high percentage,such as at least 13%, typically greater than 25%, 29%, 35%, 45%, 48%,49%, 50%, 51%, 52%, or 53%, up to 60-65%, of the dimer form of thevitamin E derivative, generally a PEG derivative of vitamin E. Theremainder of the water-soluble vitamin E derivative composition is themonomer form with a small percentage, less than 5%, 4%, 3%, 2%, 1% ofcontaminants, such as higher order polymers and reagents, such asvitamin E. Previously, water-soluble vitamin E derivative compositionshave been prepared to have as high as possible monomer concentration andtypically have at least 87% or more monomer.

It is shown herein that the water-soluble vitamin E derivative mixtures(compositions) that contain the high dimer-containing compositionsimpart advantageous properties to compositions that contain thewater-soluble vitamin E derivative composition. Hence, provided hereinare compositions that contain a water-soluble vitamin E derivativecomposition and a non-polar ingredient, such as polyunsaturated fattyacids, coenzyme Q10 compounds, phytosterols, non-polar small moleculedrugs, vitamins and other nutraceuticals and other such compounds.

Hence provided herein are compositions which can be used as concentratesfor providing soluble forms of non-polar compounds for dilution intoaqueous beverages and other foods and beverages, or can be formulatedfor direct consumption. The compositions, referred to herein asconcentrates (although they can be formulated not only for dilution, butfor direct consumption), that contain a non-polar compound and awater-soluble vitamin E derivative composition that contains at least13%, typically, at least 20%, 25%, 29%, 30%, 40%, 45%, 50% or more,typically up to 60-65%, of the dimer form of the vitamin E derivativeproduct. One advantageous property of the higher dimer-containingwater-soluble vitamin E derivative compositions is that, when dilutedinto foods and beverages, the resulting products have greater clarityand stability than products produced by addition of the sameconcentrates, except that the concentrates contain a water-solublevitamin E derivative composition that contains less than 13% dimer.

Generally, vitamin E derivative compositions have been prepared tocontain as much monomer form as possible and contain dimer only as anundesired byproduct in low concentration. The water-soluble vitamin Ederivative mixtures (compositions) provided herein can be used as thePEG derivative of vitamin E, such as TPGS, in addition to or in place ofanother surfactant, such as a polysorbate, in any composition orformulation that contains a PEG derivative of vitamin E, such as TPGS.

The water-soluble vitamin E derivative mixtures (compositions) describedand used herein are manufactured to contain higher amounts of the dimerform and, consequently, lower amounts of the monomer form of the vitaminE derivative. For example, aqueous beverages that contain these higherdimer content water-soluble vitamin E derivative mixtures (compositions)have substantially greater clarity; typically they are about 2-fold lessturbid when measured with a nephelometer in Nephelometric TurbidityUnits (NTUs), compared to the same beverages and concentrates thatdiffer only in the water-soluble vitamin E derivative composition thatis used. Amounts and particulars of the compositions and theconcentrates and resulting liquid dilution compositions, such as aqueousbeverages, are described herein. Reference is made to the descriptionand claims set forth below.

Previously, water-soluble vitamin E derivative compositions have beenprepared to have as high as possible monomer concentration and typicallyhave at least 87% or more monomer. It is shown herein that thewater-soluble vitamin E derivative mixtures (compositions) that containhigh amounts of dimer impart advantageous properties to compositionsthat contain the water-soluble vitamin E derivative composition. Hence,provided herein are compositions that contain a water-soluble vitamin Ederivative mixture (composition) and a non-polar ingredient, such aspolyunsaturated fatty acids, coenzyme Q10 compounds, phytosterols,non-polar small molecules, drugs, vitamins and other nutraceuticals, andother such compounds.

Provided herein are compositions that include concentrates and liquiddilution compositions produced from the concentrates, compositions fordirect consumption, and dilutions of the concentrates, such asbeverages, that contain water-soluble vitamin E derivative mixtures(compositions) and a non-polar ingredient and optionally, additionalingredients. The water-soluble vitamin E derivative mixtures(compositions) contain a relatively high percentage, at least 13%,typically greater than 25%, 29%, 35%, 45%, 48%, 49%, 50%, 51%, 52%, 53%,up to 60-65%, of the dimer form of the vitamin E derivative, generally aPEG derivative of vitamin E. The remainder of the water-soluble vitaminE derivative composition is the monomer form and a small percentage,less than 5%, 4%, 3%, 2%, or 1% of contaminants, such as higher orderpolymers and reagents, such as vitamin E.

These high dimer-containing water-soluble vitamin E derivativecompositions (mixtures) are employed for the preparation of compositionsthat contain the water-soluble vitamin E mixtures and one or morenon-polar ingredients, such as fatty acids, vitamins, phytosterols,other nutraceuticals, drugs, and bioactive components. The water-solublevitamin E derivative mixtures (compositions) contain a high percentage,greater than or at least 13%, by weight, of the dimer form of thevitamin E derivative, and the remainder is predominantly the monomerform, with up to 5% other components, such as trace amounts of reagents,other forms of vitamin E, and other minor contaminants. Thus, thewater-soluble vitamin E derivative mixture (composition) provides amixture of the dimer form and monomer form of the water-soluble vitaminE derivative and contains a relatively high concentration of dimer form.These mixtures (or compositions) also are referred to as highdimer-containing vitamin E derivative mixtures, because they aremanufactured to be a mixture of forms, with greater than 13%, typicallygreater than 20%, dimer form. This mixture has advantageous properties,particularly compared to the same derivative of vitamin E that has beenused that contains much lower concentrations of dimer, if any, and atleast 87% monomer form. The high dimer-containing water-solublederivatives of vitamin E mixtures are employed to solubilize non-polaringredients. Thus, provided are compositions that contain highdimer-containing water-soluble derivatives of vitamin E mixtures and anon-polar compound. In particular, the compositions, which includecompositions for direct consumption and concentrates, includingnanoemulsion concentrates, contain: a water-soluble vitamin E derivativemixture (composition) in an amount of from between 1% to 99%, inclusive,by weight, of the resulting composition, where the water-soluble vitaminE derivative mixture contains at least 13 wt % water-soluble vitamin Ederivative dimer and up to 87 wt % monomer; and a non-polar compoundother than the water-soluble vitamin E derivative mixture. In someembodiments, the water-soluble vitamin E derivative mixture contains atleast 20%, 25% or 29%, by weight, vitamin E derivative dimer, or thewater-soluble vitamin E derivative mixture contains up to 75%, 70%, 69%,62%, 55%, 50%, 45%, 40%, 35% dimer or 29%-69%, inclusive, of dimer;and/or contains less than 70%, 65%, 63%, 62%, 61%, 55%, 50%, 48%, byweight, of the vitamin E derivative monomer in the water-soluble vitaminE derivative mixture. In some embodiments, the amount of dimer isgreater than 29% and the total amount of dimer and monomer in thewater-soluble vitamin E derivative mixture is greater than 95%, 96%,97%, 98%, or 99%.

The dimer form of the water-soluble vitamin E derivative is present inan amount between or between about 13% and 15%, 13% and 20%, 13% and25%, 13% and 30%, 13% and 35%, 13% and 40%, 13% and 45%, 13% and 50%,13% and 55%, 13% and 60%, 13% and 65%, 13% and 70%, 13% and 75%, 20% and25%, 20% and 30%, 20% and 35%, 20% and 40%, 20% and 45%, 20% and 50%,20% and 55%, 20% and 60%, 20% and 65%, 20% and 70%, 20% and 75%, 25% and30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and 55%,25% and 60%, 25% and 65%, 25% and 70%, 25% and 75%, 30% and 35%, 30% and40%, 30% and 45%, 30% and 50%, 29% and 52%, 30% and 55%, 30% and 60%,30% and 65%, 30% and 70%, 30% and 75%, 35% and 40%, 35% and 45%, 35% and50%, 35% and 55%, 35% and 60%, 35% and 65%, 35% and 70%, 35% and 75%,40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%, 40% and 65%, 40% and70%, 40% and 75%, 45% and 50%, 45% and 55%, 45% and 60%, 45% and 65%,45% and 70%, 45% and 75%, 50% and 55%, 50% and 60%, 50% and 65%, 50% and69%, 55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 60% and 65%,60% and 70%, 60% and 75%, 65% and 70%, 65% and 75%, or 70% and 75%, byweight, of the water-soluble vitamin E derivative mixture or is at leastor at least about 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%,24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%,38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%,66%, 67%, 68%, 69%, 70%, 71%, 72%, 73% or 74%, up to 75%, by weight, ofthe water-soluble vitamin E derivative mixture.

The monomer is present in the high dimer-containing water-solublederivatives of vitamin E mixtures in an amount from between or betweenabout 25% and 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% and 50%,25% and 55%, 25% and 60%, 25% and 65%, 30% and 35%, 30% and 40%, 30% and45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% and 65%, 30% and 69%,35% and 40%, 35% and 45%, 35% and 50%, 35% and 55%, 35% and 60%, 35% and65%, 35% and 69%, 40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%,40% and 65%, 40% and 69%, 45% and 50%, 45% and 55%, 45% and 60%, 45% and65%, 45% and 69%, 50% and 55%, 50% and 60%, 50% and 65%, 50% and 69%,55% and 60%, 55% and 65%, 55% and 69%, 60% and 65%, 60% and 69%, or 65%and 69%, by weight, of the water-soluble vitamin E derivative mixture oris at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%,36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%,50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%,64%, 65%, 66%, 67%, 68%, up to and including 69%, by weight, of thewater-soluble vitamin E derivative mixture.

In the high dimer-containing water-soluble derivatives of vitamin Emixtures, the monomer comprises between or between about 35% and 65%,inclusive, by weight, of the water-soluble vitamin E derivative mixtureand the dimer comprises between or between about 25% and 65%, by weight,of the water-soluble vitamin E derivative mixture, or the dimercomprises between or between about 29% and 61% or 62%, by weight, of thewater-soluble vitamin E derivative mixture, and the monomer and dimercomprise at least 70%, by weight, of the water-soluble vitamin E mixturein the composition.

The water-soluble vitamin E derivative is any suitable derivative ofvitamin E that renders it more soluble than in its absence, and canresult in mixtures of dimers and monomers. Exemplary of such derivativesare polyalkylene glycol derivatives of vitamin E, such as, but notlimited to, polyethylene glycol (PEG) derivatives of vitamin E. PEGderivatives include those in which the PEG derivative of vitamin Econtains a PEG moiety having a molecular weight between or between about100 Da and 20,000 Da, inclusive, including between 200 Da and 10,000 Da,200 Da and 8000 Da, 200 Da and 6000 Da, 200 Da and 5000 Da, 200 Da and3000 Da, 200 Da and 1000 Da, 200 Da and 800 Da, 200 Da and 600 Da, 200Da and 400 Da, 400 Da and 20,000 Da, 400 Da and 10,000 Da, 400 Da and8000 Da, 400 Da and 6000 Da, 400 Da and 5000 Da, 400 Da and 3000 Da, 400Da and 1000 Da, 400 Da and 800 Da, 400 Da and 600 Da, 600 Da and 20,000Da, 600 Da and 10,000 Da, 600 Da and 8000 Da, 600 Da and 6000 Da, 600 Daand 5000 Da, 600 Da and 3000 Da, 600 Da and 1000 Da, 600 Da and 800 Da,800 Da and 20,000 Da, 800 Da and 10,000 Da, 800 Da and 8000 Da, 800 Daand 6000 Da, 800 Da and 5000 Da, 800 Da and 3000 Da, 800 Da and 1000 Da,1000 Da and 20,000 Da, 1000 Da and 10,000 Da, 1000 Da and 8000 Da, 1000Da and 6000 Da, 1000 Da and 5000 Da, 1000 Da and 3000 Da, 3000 Da and20,000 Da, 3000 Da and 10,000 Da, 3000 Da and 8000 Da, 3000 Da and 6000Da, 3000 Da and 5000 Da, 5000 Da and 20,000 Da, 5000 Da and 10,000 Da,5000 Da and 8000 Da, 5000 Da and 6000 Da, 6000 Da and 20,000 Da, 6000 Daand 10,000 Da, 6000 Da and 8000 Da, 8000 Da and 20,000 Da, 8000 Da and10,000 Da or 10000 Da and 20,000 Da, or has a molecular weight of atleast 100, 200, 238, 300, 400, 500, 600, 750, 800, 1000, 1200, 1500,2000, 2500, 3000, 3400, 3500, 4000, 6000, 8000, 10,000, 12,000, 14,000,16,000, or 18,000, up to and including 20,000 Da.

Among the PEG derivatives of vitamin E are, for example, tocopherylpolyethylene glycol succinate, tocopheryl polyethylene glycol sebacate,tocopheryl polyethylene glycol dodecanodioate, tocopheryl polyethyleneglycol suberate, tocopheryl polyethylene glycol azelaate, tocopherylpolyethylene glycol citraconate, tocopheryl polyethylene glycolmethylcitraconate, tocopheryl polyethylene glycol itaconate, tocopherylpolyethylene glycol maleate, tocopheryl polyethylene glycol glutarate,tocopheryl polyethylene glycol glutaconate, tocopheryl polyethyleneglycol fumarate, tocopheryl polyethylene glycol phthalate, tocotrienolpolyethylene glycol succinate, tocotrienol polyethylene glycol sebacate,tocotrienol polyethylene glycol dodecanodioate, tocotrienol polyethyleneglycol suberate, tocotrienol polyethylene glycol azelaate, tocotrienolpolyethylene glycol citraconate, tocotrienol polyethylene glycolmethylcitraconate, tocotrienol polyethylene glycol itaconate,tocotrienol polyethylene glycol maleate, tocotrienol polyethylene glycolglutarate, tocotrienol polyethylene glycol glutaconate, tocotrienolpolyethylene glycol fumarate and tocotrienol polyethylene glycolphthalate.

In some embodiments the vitamin E derivative is selected from amongtocopheryl polyethylene glycol succinate (TPGS), tocopheryl sebacatepolyethylene glycol and other TPGS analogs and TPGS homologs, tocopheryldodecanodioate polyethylene glycol, tocopheryl suberate polyethyleneglycol, tocopheryl azelaate polyethylene glycol, tocopheryl citraconatepolyethylene glycol, tocopheryl methylcitraconate polyethylene glycol,tocopheryl itaconate polyethylene glycol, tocopheryl maleatepolyethylene glycol, tocopheryl glutarate polyethylene glycol,tocopheryl glutaconate polyethylene glycol and tocopheryl phthalatepolyethylene glycol. Exemplary of TPGS, is D-α-tocopheryl polyethyleneglycol succinate (TPGS).

In addition to the high dimer-containing water-soluble derivatives ofvitamin E mixtures, the compositions provided herein contain anadditional ingredient, which typically is a bioactive ingredient, suchas a drug, vitamin or nutraceutical. Generally, such ingredients arenon-polar ingredients and are rendered soluble by the highdimer-containing water-soluble derivatives of vitamin E mixture. Asprovided and shown herein, the high dimer-containing water-solublederivatives of vitamin E mixtures are more effective than vitamin Ederivative compositions that contain high amounts of monomer and lowamounts, if any, of dimer.

Among the non-polar ingredients are those that are or contain anon-polar compound, such as, but not limited to, polyunsaturated fattyacids (PUFAs), coenzyme Q, phytosterols, resveratrol, carotenoids,micronutrients, alpha lipoic acid and oil-soluble vitamins. Exemplary ofsuch compounds are non-polar compounds that contain PUFAs, such as fishoil, algae (algal) oil, flaxseed oil, borage oil, saw palmetto extract,safflower oil, coconut oil, soybean oil and conjugated linoleic acid(CLA)-containing compounds. These include omega-3 fatty acids, omega-6fatty acids, omega-9 fatty acids and conjugated fatty acids, such as,but not limited to, docosahexaenoic acid (DHA), eicosapentaenoic acid(EPA), alpha-linolenic acid (ALA), gamma-linolenic acid (GLA),conjugated linoleic acid (CLA) and oleic acid compounds. Among these arecoenzyme Q10; an oil-soluble vitamin that is selected from among vitaminB12, vitamin D3, vitamin A palmitate, vitamin E, vitamin B1, vitamin B3,vitamin B5, vitamin B6, vitamin C and mixtures thereof; acarotenoid-containing compound that is selected from among lycopene,lutein, zeaxanthin and mixtures of lutein and zeaxanthin; and amicronutrient-containing compound that is selected from among yerbamate, ginkgo biloba and ginseng.

The concentration of non-polar compound in the composition depends uponthe particular compound and desired dosage or amount to be administeredand also whether the composition is intended for direct administrationor is a concentrate for dilution or consumption in a capsule. Hence, theconcentration of non-polar compound can be present in an amount from0.1%-99%, by weight, of the composition, such as 0.5% or 1% to 75%, byweight, of the composition, or, for example, 0.1% to 10%, 1% to 5%, 5%to 10%, 5% to 12%, 5% to 15%, 5% to 20%, 5% to 25%, 10% to 14%, 10% to12%, 10% to 15%, 10% to 20%, 10% to 25%, 5% to 30%, 1% to 30% or 1% to15%, inclusive, by weight, of the composition.

Other ingredients in the compositions include a preservative in anamount sufficient to preserve the composition. The preservative, forexample, can contain benzyl alcohol.

The compositions can also include a non-polar solvent that dissolves thenon-polar compound and is different therefrom and is present in anamount sufficient to dissolve the non-polar compound. Exemplarynon-polar solvents include, for example, a vitamin E oil, a flaxseedoil, an oat oil and mixtures thereof.

The compositions can include a polar solvent, such as a polar proticsolvent. Exemplary polar solvents include water and consumable alcoholsand mixtures thereof, such as, but not limited to, water, glycerin,propylene glycol, ethylene glycol, tetraethylene glycol, triethyleneglycol and trimethylene glycol. The amount of polar solvent depends uponthe particular composition and whether it is a concentrate or for directconsumption. Hence, the concentration can be, for example, from morethan 0.5% or 1% to 95%, by weight, of the composition, such as from 45%to 80%, or 60% to 80%, by weight, of the composition.

The compositions also can contain a co-surfactant present in an amountsufficient to increase stability of the composition compared to theabsence of a co-surfactant. Co-surfactants for use with the highdimer-containing water-soluble vitamin E derivative mixtures include,for example, a phospholipid, such as phosphatidyl choline, a sucrosefatty acid ester, a polysorbate and a polysorbate analog.

The compositions also can include an emulsion stabilizer, such as amodified starch and gum mixture. These include, for example, one or moreof a blend of xanthan gum, guar gum and sodium alginate; modified gumacacia; and ester gum.

The compositions include other optional ingredients, such as a pHadjuster, present to adjust the pH of the composition to between 2.0 and4.0. Typically, the pH adjuster is present in an amount of less than 1%by weight. Exemplary pH adjusters include citric acid and phosphoricacid. Other ingredients include a flavor or flavoring agent and/orsweeteners, particularly in the compositions for direct administration.Flavors can be imparted by beverage bases as well as flavoring agents.

The amount of the water-soluble vitamin E derivative mixture is from 16%to 30%, inclusive, or is 1% to 95%, inclusive, or is 10% to 40%,inclusive, or 10% to 50%, inclusive, or 15% to 25%, inclusive, byweight, of the composition, or is at least 1%, 2%, 3%, 4%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, or 95%, inclusive, by weight, of the composition, such as greaterthan 1%, 2%, 3%, 4%, 5%, 10%, 15% or 20% or about 20%, greater than 30%or about 30%, between 30% or about 30% and 55% or about 55%, between 16%and 30%, between 30% or about 30% and 50% or about 50%, between 30% orabout 30% and 45% or about 45%, or at least 10%, 12%, 15%, 17%, 20%,22%, 24%, 27%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%,41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% or55%, up to at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or99%, all by weight, of the composition. For example, for concentrates,the vitamin E derivative mixture can be present in an amount of about atleast 15%, or 15% to 30%, at least 40% or about 40%, 50% or about 50%,or greater than 60% or about 60%, greater than 65% or about 65%, forexample, greater than 70% or about 70%, for example, a startingconcentration within the concentration range of between 50% or about 50%and 95% or about 95%, between 60% or about 60% and 95% or about 95%,between 65% or about 65% and 90% or about 90%, for example, between 69%or about 69% and 90% or about 90%, between 69% or about 69% and 89% orabout 89%, for example, at least 65%, 66%, 67%, 68%, 69%, 69.5%, 69.9%,70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 79.5%, 79.9%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 89.5%, 89.9%, or 90%, byweight, of the composition.

Exemplary compositions, particularly concentrates, include a compositionthat contains a water-soluble vitamin E derivative mixture present in anamount from 5% to 95%, by weight, of the composition, wherein thewater-soluble vitamin E derivative mixture comprises from 25 wt % to 69wt % water-soluble vitamin E monomer and from 13 wt % to 75 wt %water-soluble vitamin E dimer; a non-polar compound other than thewater-soluble vitamin E derivative mixture, present in an amount from 1%to 75%, by weight, of the composition; and a preservative, present in anamount sufficient to preserve the composition.

Another composition contains: a water-soluble vitamin E derivativemixture present in an amount from 5% to 95%, by weight, of thecomposition, where the water-soluble vitamin E derivative mixturecomprises from 25 wt % to 69 wt % water-soluble vitamin E monomer andfrom 13 wt % to 75 wt % water-soluble vitamin E dimer; a non-polarcompound other than the water-soluble vitamin E derivative mixture,present in an amount from 1% to 75%, by weight, of the composition; apreservative, present in an amount sufficient to preserve thecomposition; and a non-polar solvent that differs from the non-polarcompound and is present in an amount sufficient to dissolve thenon-polar compound.

Another exemplary composition contains: a water-soluble vitamin Ederivative mixture, present in an amount from 5% to 95%, by weight, ofthe composition, where the water-soluble vitamin E derivative mixturecomprises from 25 wt % to 69 wt % water-soluble vitamin E monomer andfrom 13 wt % to 75 wt % water-soluble vitamin E dimer; a non-polarcompound other than the water-soluble vitamin E derivative mixture,present in an amount from 1% to 75%, by weight, of the composition; apreservative, present in an amount sufficient to preserve thecomposition; a polar solvent, present in an amount from 45% to 80%, byweight, of the composition; and a pH adjuster, present in an amountsufficient to adjust the pH of the composition to between 2.0 and 4.0.

The compositions provided herein can be concentrates or can be fordirect consumption. Among those for direct consumption are dilutioncompositions, such as beverage compositions, into which any of theconcentrates provide herein have been diluted. Also included are thepre-gel compositions and soft gel compositions that contain a surfactantand non-polar ingredient(s) for direct consumption.

The compositions provided herein also can contain additional ingredientssuch as sweeteners, stabilizers, pH adjusters and antifoaming agents.Sweeteners include any known to those of skill in the art, including,but not limited to, sucralose, sucrose, lactose, fructose, an acesulfamesalt, aspartame, saccharin, stevia, stevioside and xylitol. Stabilizersinclude, but are not limited to, carbonates, bicarbonates, acids andantioxidants. The carbonates, bicarbonates, acids and antioxidants canbe included in the compositions for direct consumption, as theystabilize the compositions as consumed and packaged. Such compositionsalso are packaged in a sealed container, which can contain nitrogen todisplace oxygen from the sealed container. Such compositions include,but are not limited to, juice, water, sports drinks and sodas.

Also provided are emulsion compositions that can be used to form drypowders. Also provided are soft gel compositions that contain anon-polar ingredient, a high dimer-containing water-soluble vitamin Ederivative mixture (composition), such as a the PEG derivative ofvitamin E composition, such as a high dimer-containing TPGS composition,and a relatively high concentration, such as greater than 1%, typicallygreater than 7%, 10%, 15%, of a non-aqueous solvent, such as an alkylalcohol, such as benzyl alcohol, in an amount greater than 1% and up to25%, are provided. The claims set forth below directed to each of thesecompositions are herein incorporated by reference. Also, incorporated byreference are the subject matter, and all claims in U.S. ProvisionalApplication Ser. No. 62/052,435, filed Sep. 18, 2014, entitled “SOFT GELCOMPOSITIONS AND PRE-GEL CONCENTRATES” to Philip J. Bromley, and U.S.Provisional Application Ser. No. 62/052,433, filed Sep. 18, 2014,entitled “PRE-SPRAY EMULSIONS AND POWDERS CONTAINING NON-POLARCOMPOUNDS” to Philip J. Bromley. It is understood that for purposesherein, the water-soluble vitamin E derivative compositions in theincorporated claims are the high dimer-containing compositions asdescribed herein.

Provided are powders and pre-spray emulsions. The pre-spray emulsionscomprise the ingredients of the powders plus a polar solvent. Thecapsules, tablets and soft gel capsules are for administering to asubject to provide a non-polar ingredient or compound to the subject,such as for supplementation to provide a nutrient or nutraceutical or abioactive compound for treating or lowering the risk of a disease. Thepowders, which are soluble, can be introduced into a beverage of choiceto provide the non-polar ingredient or compound or sprinkled on food.

Exemplary of the non-polar ingredients in all of the compositionsprovided herein are the following: omega-3 EPA and DHA; resveratrol;sesamin; curcumin; Boswellia (Boswellic acids); lipoic acid, such asalpha lipoic acids, capsaicinoids; PQQ, carotenoids, such asastaxanthin, zeaxanthin; lutein, beta carotene, and lycopene; andvitamins, such as vitamin A, vitamin D and vitamin E complexes; vitaminK1 and vitamin K as MK7.

Methods for preparing the compositions, particularly those that areconcentrates, are provided. These methods include steps of: (a) mixingand heating initial ingredients in a vessel, where the initialingredient(s) comprise: a water-soluble vitamin E derivative mixturepresent in an amount from 5% to 95%, by weight, of the concentrate; andthe water-soluble vitamin E derivative mixture comprises from 25 wt % to69 wt % water-soluble vitamin E monomer and from 13 wt % to 75 wt %water-soluble vitamin E dimer; and then (b) adding one or moreadditional ingredients to the vessel, where the one or more additionalingredients comprise: a non-polar compound at an amount from 1% to 75%,by weight, of the concentrate; and then (c) homogenizing theingredients; and (d) cooling the mixed ingredients, whereby, forcompositions with high levels of vitamin E derivatives, the mixedingredients become waxy in consistency, and lower levels form anemulsion, thereby generating the composition.

Methods for preparing a beverage, soft gel, and other compositions fordirect consumption containing non-polar ingredients also are provided.The beverages are prepared by adding the composition provided herein,such as a nanoemulsion concentrate, to a beverage base. The concentrateis added at a predetermined concentration to produce a beveragesupplemented with the non-polar ingredient in the concentrate at aneffective or intended concentration. The beverage base comprises theother components of the resulting beverage, including, but not limitedto, water, juice, soda, a sports drink and/or a nutritional drink. Softgel compositions are prepared by introducing a pre-gel composition intoa soft gel shell or capsule.

DETAILED DESCRIPTION

Outline A. Definitions B. Water-soluble vitamin E derivatives 1. VitaminE 2. Polyalkyleneglycol derivatives of vitamin E a. Tocopherols andtocotrienols b. Linkers c. PEG moieties d. Surfactant properties 3.Tocopheryl polyalkyleneglycol derivatives a. Uses i. Nutritionalsupplement ii. Surfactant 4. Synthesis 5. Water-soluble vitamin Ederivative mixtures (compositions) C. Methods for making water-solublevitamin E derivatives 1. Reaction mixture a. Vitamin E succinate b.Polyethyleneglycol c. Catalyst d. Solvent e. Exemplary reaction mixtures2. Exemplary methods a. Preparation of a crude water-soluble vitamin Ederivative mixture b. Processing the reaction mixture to obtain a crudewater-soluble vitamin E derivative mixture c. Purification of the crudewater-soluble vitamin E derivative mixture to obtain a purified highdimer-containing water-soluble vitamin E derivative mixture D. Productscontaining high dimer-containing water-soluble vitamin E derivativemixtures 1. Exemplary ingredients and exemplary concentration ranges a.Water-soluble vitamin E derivatives b. Non-polar ingredients i.Polyunsaturated fatty acid (PUFA)- containing ingredients (a) Omega-3fatty acid compounds (1) DHA/EPA (i) Fish oils (ii) Algae oil (2) Flaxseed oil - omega 3 (ALA) (b) Omega-6 compounds (c) Saw palmetto extract(d) Conjugated linoleic acid (CLA) ii. Coenzyme Q compounds iii.Phytochemical-containing non-polar ingredients (a) Phytosterols (b)Resveratrol iv. Carotenoid-containing compounds (a) Carotenes (b)Xanthophylls v. Micronutrient-containing compounds (a) Vitamins (b)Alpha-lipoic acid (thioctic acid) vi Boswellia extracts vii. Alkaloidsviii. Cannabinoids ix. Hops-containing compounds x. Antioxidants c.Non-polar solvents d. Preservatives and sterilizers e. Polar solvents f.Co-surfactants (emulsifiers) i. Phospholipids ii. Sugar-derivedsurfactants iii. PEG-derived surfactants iv. Sucrose fatty acid estersurfactants g. Emulsion stabilizers (co-emulsifiers) h. Flavors i. pHadjusters j. Soluble fibers k. Additional ingredients i. Additionalnon-polar compounds ii. Stabilizers (a) Bicarbonates or carbonates (b)Acids (c) Antioxidants 2. Concentrates a. Pre-emulsion concentrates i.Formulating the pre-emulsion concentrates ii. Exemplary ingredients andtypical concentration ranges b. Liquid nanoemulsion concentrates i.Formulating the liquid nanoemulsion concentrates c. Liquid dilutioncompositions containing the concentrates d. Evaluation of theconcentrates and liquid dilution compositions i. Clarity (a) Empiricalevaluation (b) Particle size or number of particles (c) Turbiditymeasurement ii. Stability iii. Advantageous characteristics ofcompositions for human consumption iv. Safety v. Oral bioavailability e.Selecting a formulation and modifying formulations 3. Soft gel andpre-gel compositions containing non-polar ingredients and the highdimer-containing PEG derivative of vitamin E mixture a. Non-aqueouspre-gel compositions containing non-polar ingredients i. Non-polaringredients ii. Surfactants (high dimer-containing water-soluble vitaminE derivative mixtures) iii. Non-aqueous solvents iv. Co-surfactants(emulsifiers) (a) Phospholipids (b) Sugar-derived surfactants (c)PEG-derived surfactants (d) Sucrose fatty acid ester surfactants v.Emulsion stabilizers (co-emulsifiers) vi. Flavors vii. pH adjustersviii. Soluble fibers ix. Stabilizers (a) Bicarbonates or carbonates (b)Acids (c) Antioxidants b. Formulating the non-aqueous pre-gelconcentrates containing non-polar ingredients c. Soft gel compositionscontaining non-polar ingredients i. Capsules d. Formulating the soft gelcompositions e. Ingredients and concentration ranges f. Exemplarydosages and administration of the soft gel compositions 4. Powders andpre-spray emulsions a. Pre-spray emulsions containing non-polaringredients i. Formulating the pre-spray emulsions ii. Exemplaryingredients and typical concentration ranges (a) Pre-emulsionconcentrates (b) Surfactants (1) Sucrose fatty acid ester surfactants(c) Stabilizers (1) Bicarbonates and carbonates (2) Ingestible acids (3)Antioxidants (d) Polar solvents (e) Binders (f) Co-surfactants(emulsifiers) (1) Phospholipids (2) PEG-derived surfactants (g) Emulsionstabilizers (co-emulsifiers) (h) pH adjusters b. Powder compositionscontaining non-polar ingredients i. Formulating the powder compositionsii. Ingredients and concentration ranges E. Exemplary methods forpreparing products containing high dimer- containing water-solublevitamin E derivative mixtures 1. Equipment employed in the methods a.Scales b. Purifiers c. Vessels d. Mixers e. Heating/cooling apparatusesf. Transfer devices g. Evaluation equipment 2. General methods forproducing the compositions a. Water phase ingredients b. Water phaseproduction c. Oil phase ingredients d. Oil phase production e. Combiningphases f. Cooling g. Filtration, additions, evaluation and packaging h.Cleaning the equipment i. Clarity 3. General methods for preparingaqueous pre-gel concentrates (compositions that are introduced into orformulated in soft gel shells or capsules) a. Ingredients b. Productionof the non-aqueous pre-gel concentrates c. Transfer and/or packaging 4.Exemplary methods for preparing pre-spray emulsions and powders a.General methods for producing the emulsions and powders b. Drying theemulsions to produce powders c. Storing the powders d. Filtration,additions, evaluation and packaging F. Examples

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the invention(s) belong. All patents, patent applications,published applications and publications, Genbank sequences, databases,websites and other published materials referred to throughout the entiredisclosure herein, unless noted otherwise, are incorporated by referencein their entirety. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

As used herein, “vitamin E” refers to any naturally occurring orsynthetic form of vitamin E, for example, tocopherols and tocotrienols,and can refer to a single form of the compound or a mixture of forms.

As used herein, “water-soluble vitamin E derivative composition,”“water-soluble vitamin E derivative,” “water-soluble vitamin Ederivative surfactant,” “water-soluble vitamin E surfactant,” and“water-soluble derivative of vitamin E mixture,” which are be usedinterchangeably, refer to compositions that contain mixtures ofwater-soluble forms of vitamin E (vitamin E derivatized with moieties,such as polyalkylene glycol that increase the water solubility of thewater-insoluble vitamin E). The mixtures contain dimers and monomers ofthe vitamin E derivatives. The water-soluble vitamin E derivativemixtures (compositions) include vitamin E (natural or synthetic forms ofvitamin E), such as tocopherol derivatives and tocotrienol derivatives.Derivatives of vitamin E, such as polyethylene glycol (PEG)-derivativespreviously produced, are manufactured to contain as much monomer form aspossible, and to contain minimal amounts of any dimer form (see, e.g.,Christiansen et al. (2011) J. Pharm. Sci. 100(5):1773-1782).

In contrast, the high dimer-containing vitamin E derivative mixtures,such as PEG derivative of vitamin E compositions (also referred toherein as high dimer PEG derivatives of vitamin E mixtures or highdimer-containing PEG derivatives of vitamin E mixtures) employed herein,are manufactured to contain dimer forms. The mixtures described hereincontain at least 13%, particularly at least or at least about 20%, 25%,29%, or more, dimer form of the water-soluble vitamin E derivative. Inparticular, the water-soluble vitamin E derivative mixtures(compositions) are manufactured to contain between or between about 13wt % and about or up to 95%, 90%, 85%, 80%, or 75 wt %, particularly atleast 29% to 75% or 80%, inclusive, of the water-soluble vitamin Edimer. In general, the high dimer-containing derivatives, such as PEGderivatives of vitamin E mixtures, such as a high dimer-containing TPGScomposition, contain 30%-60%, particularly 35%-52%, dimer, and theremainder is the monomer form and is present in less than 5%, generally3%, 2%, or 1%, and other trace components, such as unreacted reagents,such as vitamin E and the hydrophilic derivatizing moiety.

In general, the mixtures herein contain at least 13% of the dimer formand up to 87% monomer form, particularly at least 25% of the dimer formand up to 70% of the monomer form, such as between or between about 25wt % and 69%, inclusive, of the monomer. Hence, the water-solublevitamin E derivative mixtures (compositions) (high dimer-containingcompositions) contain a substantial amount (i.e., 13% or more,particularly 25%, 29%, 35%, 48%, 52%, or more) of the dimer formcompared to commercially available forms that are manufactured toprovide the monomer form.

As manufactured, the high dimer-containing mixtures can include otherforms and unreacted components, hence the total amount of dimer andmonomer do not necessarily total 100%, by weight, of the composition. Itis shown herein that inclusion of at least 13%, 20%, 25%, 29%, or moreof the dimer form, and some monomer form, about less than 87%, 69%, 65%,60%, 55%, or 50% of the monomer with at least 13% dimer, confersadvantageous properties on these water-soluble vitamin E derivativemixtures (compositions) not possessed by such compositions that containlower amounts of the dimer form.

Examples of water-soluble vitamin E derivatives are those formed bycovalently attaching a vitamin E moiety, e.g., a tocopherol ortocotrienol, to a hydrophilic moiety, for example, an alkylene glycol,such as a polyethylene glycol (PEG) moiety, via a linker. Thecompositions as provided herein are manufactured so that the resultingwater-soluble vitamin E derivative mixtures (compositions) include amixture of monomers and dimers of the water-soluble vitamin Ederivatives, and contain a substantial amount (compared to prior artpreparations), i.e., 13% to 95%, inclusive, such as at least 13%, 20%,25%, or 29%, up to as much as 75%, 80%, 85%, 90%, 95%, by weight, of thedimer form and generally less than 70%, 65%, 63%, 62%, 61% or 60%, orless of the monomer form. Water-soluble vitamin E derivative mixtures(compositions) include, for example, polyalkylene glycol derivatives oftocopherol, e.g., polyethylene glycol (PEG) derivatives of tocopherol,and polyalkylene glycol derivatives of tocotrienol, e.g., polyethyleneglycol (PEG) derivatives of tocotrienol. The water-soluble vitamin Ederivatives can include, for example, vitamin E TPGS (D-α-tocopherylpolyethylene glycol succinate), TPGS analogs, TPGS homologs and TPGSderivatives.

As used herein, “tocopherol” and “tocotrienol” refer to any naturallyoccurring or synthetic form of vitamin E, and can refer to a singlecompound or a mixture of tocopherols and tocotrienols. Examples oftocopherols include, for example, α-tocopherol, D-α-tocopherol,β-tocopherol, γ-tocopherol and δ-tocopherol. Examples of tocotrienolsinclude, for example, α-tocotrienol, β-tocotrienol, γ-tocotrienol andδ-tocotrienol.

As used herein, a “PEG derivative of vitamin E” or “vitamin E-PEGconjugate” or “vitamin E-PEG derivative,” is a compound containing oneor more vitamin E moieties (e.g., a tocopherol or tocotrienol) joined bya covalent bond, for example, an ester, ether, amide or thioester bond,to one or more polyethylene glycol (PEG) moieties, via a linker, such asa dicarboxylic or tricarboxylic acid. Exemplary of PEG derivatives ofvitamin E are D-α-tocopheryl polyethylene glycol succinate (TPGS), TPGSanalogs, TPGS homologs and TPGS derivatives.

As used herein, “tocopheryl polyethylene glycol succinate,” “TPGS,”“tocopheryl polyethylene glycol succinate surfactant” and “TPGSsurfactant” refer to tocopheryl polyethylene glycol conjugates that areformed by covalently joining tocopherol succinate, an ester formedthrough esterification of tocopherol and succinic acid, to apolyethylene glycol (PEG) moiety via an esterification reaction. The PEGmoiety of the TPGS surfactant can be any PEG moiety, for example, a PEGmoiety with a molecular weight of between or between about 200 Da to20,000 Da or about 20,000 Da, for example, PEG moieties having amolecular weight of or about 200, 300, 400, 500, 600, 800, 1000, 3000,5000, 6000, 8000, 10,000, 20,000 Da, or more; or PEG analogs, including,for example, PEG-NHS (N-hydroxysuccinimide), PEG-aldehyde, PEG-SH,PEG-NH₂, PEG-CO₂H, and branched PEGs.

As used herein, “TPGS monomer” is a single vitamin E moiety, i.e.,D-α-tocopherol, covalently joined to a water-soluble moiety, such as apolyethylene glycol, through a succinate linker. “TPGS monomer” can alsorefer to TPGS analogs, homologs or derivatives, including any otherwater-soluble vitamin E derivatives described herein. A “TPGS dimer” ismade up of two vitamin E moieties, i.e., D-α-tocopherol, covalentlyjoined to a water-soluble moiety, such as a polyethylene glycol, throughone or more succinate linkers (shown below). “TPGS dimer” can also referto TPGS analogs, homologs or derivatives, including any otherwater-soluble vitamin E derivatives described herein. The esterificationreaction between the vitamin E moiety, for example, D-α-tocopherylsuccinate, and PEG results in a highly complex crude product thatcontains a mixture of TPGS monomer, unreacted PEG, unreacted vitamin E(e.g., D-α-tocopheryl succinate), catalyst, and TPGS dimer, formed whena second molecule of the vitamin E moiety reacts with the terminalhydroxyl group of a PEG moiety already conjugated to TPGS monomer via alinker. For purposes herein, mixtures are produced by performing thereaction under conditions that result in higher amounts of the TPGSdimer being produced as compared to prior art preparations. In addition,the TPGS dimer can be purified and the amounts increased. Thewater-soluble vitamin E derivative mixtures (compositions) where thevitamin E derivative is TPGS, as described herein, contain a mixture ofTPGS monomer and TPGS dimer, and contain more than 12%, but generally atleast 20%, 25%, 29%, 35%, or more, TPGS dimer, up to as much as 95% orabout 95% TPGS dimer, but typically up to about 75%. The remainder ofthe composition contains the TPGS monomer and can contain unreactedstarting materials and catalyst. Similarly, water-soluble vitamin Ederivative mixtures (compositions) containing vitamin E derivativesother than TPGS contain mixtures of dimer and monomer.

As used herein, a “concentrate” is a composition that comprises thewater-soluble high dimer-containing vitamin E derivative mixture and/orthe non-polar ingredient that is or contains a non-polar compound(s) inhigher than single dosage concentrations so that the concentratecompositions are diluted for ingestion.

As used herein, “colloid” refers to a mixture containing two phases, adispersed phase and a continuous phase, with the dispersed phasecontaining particles (droplets) distributed throughout the continuousphase. Colloidal mixtures include aerosols, foams, and dispersions, forexample, emulsions, for example, nanoemulsions. A liquid colloid, forexample, a nanoemulsion, can have a similar appearance, for example,similar clarity, to a solution in which there is no dispersed phase.

As used herein, “emulsion” refers to a colloidal dispersion of twoimmiscible liquids, for example, an oil and water (or other aqueousliquid, e.g., a polar solvent), one of which is part of a continuousphase and the other of which is part of a dispersed phase. The providedliquid dilution compositions include emulsions, typically oil-in-waternanoemulsions (which include any oil-soluble phase dispersed in anyaqueous phase, also called the water phase), in which the oil phase isthe dispersed phase and the water phase is the continuous phase.Emulsions typically are stabilized by one or more surfactants and/orco-surfactants and/or emulsion stabilizers. Surfactants form aninterfacial film between the oil and water phase of the emulsion,providing stability. Typically, the nanoemulsions of the provided liquiddilution compositions contain micelles that contain one or moresurfactants surrounding a non-polar ingredient which is dispersed in thewater phase. Exemplary of the provided emulsions are the provided liquidnanoemulsion concentrates and liquid dilution compositions and flavoredshots, made by diluting the concentrates, typically in an aqueousmedium. In general, emulsions (e.g., oil-in-water emulsions) arecolloidal dispersions of two immiscible liquids (e.g., oil and anaqueous liquid, such as water) that contain a continuous and a dispersedphase. Emulsions can be used to disperse non-polar compounds in aqueousliquids. In an oil-in-water emulsion, the dispersed phase is an oilphase and the continuous phase is an aqueous (e.g., water) phase.

As used herein, a “nanoemulsion” is an emulsion in which the disperseddroplets, for example, the micelles, have a diameter (particle size) ofless than 1000 nm or less than about 1000 nm, typically, less than 500nm or less than about 500 nm, typically less than 300 nm or less thanabout 300 nm, for example, less than 250 nm or less than about 250 nm,for example, less than or less than about 200 nm, for example, less thanor less than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, or 200 nm. Exemplary ofnanoemulsions are the provided liquid nanoemulsion concentrates and theliquid dilution compositions, for example, the aqueous liquid dilutioncompositions containing the diluted concentrates.

As used herein, “surfactant” refers to synthetic and naturally occurringamphiphilic molecules that have hydrophobic portion(s) and hydrophilicportion(s). Due to their amphiphilic (amphipathic) nature, surfactantstypically can reduce the surface tension between two immiscible liquids,for example, the oil and water phases in an emulsion, stabilizing theemulsion. Surfactants can be characterized based on their relativehydrophobicity and/or hydrophilicity. For example, relatively lipophilicsurfactants are more soluble in fats, oils and waxes, and typically haveHLB values less than or about 10, while relatively hydrophilicsurfactants are more soluble in aqueous compositions, for example,water, and typically have HLB values greater than or about 10.Relatively amphiphilic surfactants are soluble in oil- and water-basedliquids and typically have HLB values close to 10 or about 10.

As used herein, “co-surfactant” is used to refer to a surfactant that isused in the provided compositions in combination with the primarysurfactant, for example, the water-soluble vitamin E derivative mixtures(compositions) described herein, for example, to improve theemulsification of the provided compositions and/or compounds, forexample, to emulsify the ingredients. In one example, the providedcompositions can contain at least one surfactant and at least oneco-surfactant. Typically, the co-surfactant represents a lower percent,by weight (w/w), of the provided compositions, compared to thesurfactant. Thus, the provided compositions typically have a lowerconcentration of the co-surfactant(s) than of the surfactant.

As used herein, “HLB” refers to a value that is used to index anddescribe a surfactant according to its relativehydrophobicity/hydrophilicity, relative to other surfactants. Asurfactant's HLB value is an indication of the molecular balance of thehydrophobic and hydrophilic portions of the surfactant, which is anamphipathic molecule. Each surfactant and mixture of surfactants (and/orco-surfactants) has an HLB value that is a numerical representation ofthe relative weight percent of hydrophobic and hydrophilic portions ofthe surfactant molecule(s). HLB values are derived from a semi-empiricalformula. The relative weight percentages of the hydrophobic andhydrophilic groups are indicative of surfactant properties, includingthe molecular structure, for example, the types of aggregates thesurfactants form and the solubility of the surfactant. See, for example,Griffin (1949) J. Soc. Cos. Chem. 1:311. Surfactant HLB values rangefrom 1-45, while the range for non-ionic surfactants typically is from1-20. The more lipophilic a surfactant is, the lower its HLB value.Conversely, the more hydrophilic a surfactant is, the higher its HLBvalue.

As used herein, “micelle” refers to aggregates formed by surfactantsthat typically form when a surfactant is present in an aqueouscomposition, typically when the surfactant is used at a concentrationabove the critical micelle concentration (CMC). In micelles, thehydrophilic portions of the surfactant molecules contact the aqueous orthe water phase, while the hydrophobic portions form the core of themicelle, which can encapsulate non-polar ingredient(s), for example, thenon-polar ingredients in the provided concentrates. Typically, thesurfactants in the provided concentrates form micelles containing thenon-polar ingredient at their center in the aqueous liquid dilutioncompositions. Typically, the micelles in the provided concentrates havea particle size of about 1000 nm, typically less than or less than about500 nm, typically less than 300 or less than about 300 nm, for example,less than 250 nm or less than about 250 nm, for example, less than 200nm or less than about 200 nm, for example, less than or less than about5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150,160, 170, 180, 190, or 200 nm.

As used herein, “analog” refers to a chemical compound that isstructurally similar to another compound (referred to as a parentcompound), but differs slightly in composition, for example, due to thevariation, addition or removal of an atom, one or more units (e.g.,methylene units, —(CH₂)_(n)—) or one or more functional groups. Theanalog can have different chemical or physical properties compared withthe original compound and/or can have improved biological and/orchemical activity.

Alternatively, the analog can have similar or identical chemical orphysical properties compared with the original compound and/or can havesimilar or identical biological and/or chemical activity. For example,the analog can be more hydrophilic or it can have altered reactivity ascompared to the parent compound. The analog can mimic the chemicaland/or biological activity of the parent compound (i.e., it can havesimilar or identical activity), or, in some cases, can have increased ordecreased activity. The analog can be a naturally or non-naturallyoccurring (e.g., synthetic) variant of the original compound. Othertypes of analogs include isomers (e.g., enantiomers, diastereomers) andother types of chiral variants of a compound, as well as structuralisomers. The analog can be a branched or cyclic variant of a linearcompound. For example, a linear compound can have an analog that isbranched or otherwise substituted to impart certain advantageousproperties (e.g., improved hydrophobicity or bioavailability). Exemplaryof the analogs used in the provided compositions and methods are TPGSanalogs, which can be formed using the methods provided herein and canbe used in place of TPGS in the provided compositions.

As used herein, “tocopheryl polyethylene glycol succinate analog” or“TPGS analog” refers to compounds, other than TPGS, that are similar toa parent TPGS compound, but differ slightly in composition, for example,by the variation, addition or removal of an atom, one or more units(e.g., methylene units, —(CH₂)_(n)—), or one or more functional groups.TPGS analogs include vitamin E-derived surfactants, e.g., tocopherylsand tocotrienols, including PEG derivatives of vitamin E, includingvitamin E PEG monomers and dimers, such as, but not limited to,tocopheryl polyethylene glycol sebacate (PTS), tocopheryl polyethyleneglycol dodecanodioate (PTD), tocopheryl polyethylene glycol suberate(PTSr), tocopheryl polyethylene glycol azelaate (PTAz), andpolyoxyethanyl tocotrienyl sebacate (PTrienS), as well as other PEGderivatives of vitamin E. The compositions provided herein include atleast 13%, typically more than 29%, such as 29%-55%, dimer form in thecomposition, with the rest of the composition the monomer form or smallamounts of other forms and trace contaminants.

Exemplary of TPGS analogs are compounds having the formula shown inFormula II:

where R₁, R₂ and R₃ each independently is hydrogen (H) or methyl (CH₃);R₄ is H, CH₃ or the portion marked “A”; each dashed line (

) is independently a single or double bond; n is an integer from 1 to5000; m and q each independently are 0 or 1; and p is an integer from 1to 20.

As used herein, “TPGS 1000 analogs” are compounds other than TPGS 1000that are similar to a parent TPGS 1000 compound due to the addition orremoval of an atom, one or more units (e.g., methylene units—(CH₂)_(n)—), or one or more functional groups. TPGS 1000 analogsinclude, but are not limited to, TPGS compounds having one or more PEGmoieties that vary in chain length and molecular weight compared to TPGS1000, including, for example, TPGS compounds having PEG moieties havinga molecular weight between or about between 200 Da to 20,000 Da or about20,000 Da, for example, PEG moieties having a molecular weight of orabout 200, 300, 400, 500, 600, 800, 1000, 3000, 5000, 6000, 8000,10,000, 20,000 Da, or more. Also exemplary of TPGS 1000 analogs are TPGScompounds including PEG analogs, e.g., PEG-NHS, PEG-aldehyde, PEG-SH,PEG-NH₂, PEG-CO₂H, and branched PEGs. Also exemplary of TPGS 1000analogs are any TPGS analogs, e.g., vitamin E-derived surfactants,including PEG derivatives of vitamin E, including, but not limited to,tocopheryl polyethylene glycol sebacate (PTS), tocopheryl polyethyleneglycol dodecanodioate (PTD), tocopheryl polyethylene glycol suberate(PTSr), tocopheryl polyethylene glycol azelaate (PTAz) andpolyoxyethanyl tocotrienyl sebacate (PTrienS), as well as other PEGderivatives of vitamin E.

As used herein, “homolog” refers to an analog that differs from theparent compound only by the presence or absence of a simple unit, suchas a methylene unit, or some multiple of such units, e.g., —(CH₂)_(n)—.Typically, a homolog has similar chemical and physical properties as theparent compound. Exemplary of the homologs used in the providedcompositions and methods are TPGS homologs.

As used herein, “TPGS homologs” are analogs of TPGS that differ from aTPGS parent compound only by the presence or absence of a simple unit,such as a methylene unit, or some multiple of such units, e.g.,—(CH₂)_(n)—. Typically, suitable TPGS homologs have similar surfactantproperties compared to the parent compound (TPGS), for example, similarHLB values, for example, HLB values between 12 or about 12 and 20 orabout 20. Exemplary of TPGS homologs are tocopheryl polyethylene glycolsebacate (PTS), tocopheryl polyethylene glycol dodecanodioate (PTD),tocopheryl polyethylene glycol suberate (PTSr), tocopheryl polyethyleneglycol azelaate (PTAz). Exemplary of TPGS homologs are compounds havingthe formula in Formula I (above), where neither of the dashed linesrepresent a double bond and where, when m and q both are 0, and p isgreater than 1.

As used herein, “TPGS 1000 homologs” are analogs of TPGS 1000 thatdiffer from a TPGS 1000 parent compound only by the presence or absenceof a simple unit, such as a methylene unit, or some multiple of suchunits, e.g., —(CH₂)_(n)—. Suitable TPGS 1000 homologs have similarsurfactant properties compared to the parent compound (TPGS 1000), forexample, similar HLB values, for example, HLB values between 12 or about12 and 20 or about 20, such as 13-18. TPGS 1000 homologs include TPGS1000 homologs with slight variations in the length of the PEG chainmoiety.

As used herein, “organoleptic properties” refers to sensory attributesof a food or beverage, in particular the beverage compositions andpowder provided herein. Those of skill in the art understand suchproperties and they can be quantitated if needed. Organolepticproperties include, but are not limited to, taste, odor and/orappearance. “Desirable” or “advantageous” organoleptic propertiesinclude those organoleptic properties of a food or beverage compositionfor consumption by an average human subject, such as a desirable odor,taste and/or appearance, or the lack of an undesirable odor, tasteand/or appearance. Undesirable organoleptic properties include thepresence of, for example, an undesirable taste, odor or appearanceattribute, such as the presence of an “off-taste” or “off-odor,” forexample a fishy, grassy, metal or iron, sharp or tingling taste or odor,or the presence of an undesirable appearance attribute, such asseparation or precipitation. In one example, the provided beveragecompositions retain the same or about the same taste, odor and/orappearance as the same beverage composition that does not contain theprovided concentrates, that is, the provided beverage compositionsretain organoleptic properties desirable for consumption by an averagehuman subject. Desirable and undesirable organoleptic properties can bemeasured by a variety of methods known to those skilled in the art,including, for example, organoleptic evaluation methods by whichundesirable properties are detectable by sight, taste and/or smell andchemical tests, as well as by chemical analytical methods. For example,the provided beverage compositions retain the same or about the sameorganoleptic properties as the same beverage composition that does notcontain the provided concentrates over a period of time, for example, atleast or over 1, 2, 3, 4, 5, 6, or more days, at least or over 1, 2, 3,4, or more weeks, at least or over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, or more months, or at least or over 1, 2, 3, 4, or more years.

In one example, the compositions retain the same or about the same tasteas the same beverage composition that does not contain the providedconcentrate or powder. In one example, the provided beveragecompositions retain the same or about the same odor as the same beveragecomposition that does not contain the provided concentrates. In oneexample, the provided beverage compositions retain the same or about thesame appearance as the same beverage composition that does not containthe provided concentrates. In one example, the beverage compositionsretain the same organoleptic properties at room temperature, forexample, at 25° C. or at about 25° C. In another example, thecompositions retain the same organoleptic properties at between 19° C.or about 19° C. and 25° C. or about 25° C. In another example, thebeverage compositions retain the same organoleptic properties atelevated temperatures, for example, at 40° C. or at about 40° C. Inanother example, the compositions retain the same organolepticproperties at refrigerated temperatures, for example, at 4° C. or atabout 4° C., or at frozen temperatures, for example, at −20° C. or atabout −20° C. Typically, retaining the same or about the sameorganoleptic properties means that the shelf-life of beveragecompositions that contain the provided concentrates is the same or aboutthe same or longer than the beverage compositions not containing theprovided concentrates. Any or all of the above organoleptic properties,particularly the desirable organoleptic properties, are retained for theshelf-life of the beverage composition that does not contain theprovided concentrates under conditions in which the beverage compositionis normally stored. Generally, beverage compositions remain free fromorganoleptic changes for at least 6 months, unless the beveragecomposition that does not contain the provided concentrates has ashorter shelf life. The beverage composition retains its desiredorganoleptic properties for this period of time.

As used herein, “retaining the organoleptic properties” refers toretention of these properties upon storage for a recited period of time,typically at room temperature.

As used herein, “shelf life” refers to a time period within which theprovided compositions retain desirable organoleptic properties, forexample, the ability of the provided compositions to retain desirableorganoleptic properties for a period of time, for example, for at leastor more than 1, 2, 3, 4, or more weeks, typically at least or more than1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months, or at least ormore than 1, 2, 3, 4, or more years. In one example, the compositionsretain desirable organoleptic properties if they exhibit one or more ofthese described characteristics, over time, when kept at a particulartemperature. In one example, the compositions retain desirableorganoleptic properties at room temperature, for example, 25° C. orabout 25° C. In another example, the compositions retain desirableorganoleptic properties at between 19° C. and 25° C. In another example,the compositions retain desirable organoleptic properties atrefrigerated temperatures, for example, 4° C. or about 4° C., or atfrozen temperatures, for example, at −20° C. or about −20° C. In anotherexample, the compositions retain desirable organoleptic properties atelevated temperatures, for example, at 40° C. or at about 40° C.

As used herein, “particle size” and “average particle size” refersynonymously to the average diameter of particles in a provided liquid,for example, the droplet diameter or micelle diameter in an emulsion.Particle size diameter can be expressed in terms of a unit of length,for example, nanometers (nm). Alternatively, information about particlesin concentrates and liquid dilution compositions can be expressed interms of particle density, for example, ppm (parts per million), orpercent solids, in the compositions.

As used herein, “visible particles” are particles, for example, in aliquid, such as an emulsion, that are visible when viewing the liquidwith the naked eye (i.e., without magnification). For example, thevisible particles can be particles that are observed by the artisanformulating the compositions, for example, the concentrates or theaqueous liquid dilution compositions containing the dilutedconcentrates. In one example, the provided compositions contain novisible particles. In another example, the compositions contain fewvisible particles, for example, no more visible particles than anotherliquid, for example, a beverage. The presence of visible particles andthe number of visible particles is determined by empirical observation.

As used herein, “turbidity” is a measure of the cloudiness or hazinessof a liquid, caused by particles in suspension in the liquid. Turbiditycan be measured optically, for example, using a nephelometer, aninstrument with a light and a detector. The nephelometer measuresturbidity by detecting scattered light resulting from exposure of theliquid to an incident light. The amount of scattered light correlates tothe amount of particulate matter in the liquid. For example, a beam oflight passes through a sample with low turbidity with littledisturbance. Other methods for measuring turbidity are well known andcan be used with the provided methods and compositions. The units of aturbidity value measured with a nephelometer are Nephelometric TurbidityUnits (NTU). For purposes herein, the compositions provided hereintypically have low turbidity, for example, a turbidity value (NTU) ofless than or about 80. For example, the compositions provided herein canhave a turbidity value (NTU) of less than or about 30.

As used herein, a “turbid liquid” is one that is thick or opaque withvisible particles in suspension, for example, a liquid that is cloudy ormuddy in appearance.

As used herein, “clear” can be used to describe the compositionsprovided herein, for example, the aqueous liquid dilution compositionscontaining the diluted nanoemulsion concentrates and/or the nanoemulsionconcentrates themselves. In one example, a clear liquid is one that doesnot appear cloudy by empirical observation, such as to the naked eye,and/or does not contain particles or crystals that are visible to thenaked eye, or that does not exhibit “ringing.” In another example, aclear liquid is one that has a low or relatively low turbidity value,for example an NTU value, that is less than or equal to a desired NTUvalue. For example, a liquid is described as clear that has an NTU valueof less than or about 80. For example, a liquid can be clear and have anNTU value of less than or about 30. In another example, a clear liquidis one that has a small or relatively small average particle size, forexample, less than or about 1000 nm. For example, a liquid can bedescribed as clear and have an average particle size of less than orabout 200 nm. In another example, clarity is expressed relatively. Forexample, it can be desired that a particular composition is equally asclear, about as clear, or more clear than another liquid (as measuredempirically, or by measuring turbidity value or particle size). Forexample, clarity can be assessed relative to another aqueous liquiddilution composition, for example, a beverage. In one example, a liquidis clear if it is similar in appearance to another clear liquid, forexample, a beverage, for example, water. In another example, it can bedesired that a composition has a particle size that is less than orequal to another liquid, for example, a beverage. In another example, itcan be desired that a composition has a turbidity value that is lessthan or equal to another liquid, for example, a beverage. In anotherexample, it can be desired that a composition appears more clear or asclear as another liquid, for example, a beverage, for example, by havingno more visible particles, no more crystal formation and/or no morecloudiness than the other liquid. In one example, the providedcompositions are clear. In another example, they are relatively clear oras clear as or about as clear as another liquid, for example, a beveragethat does not contain the non-polar ingredient or liquid nanoemulsioncomposition.

As used herein, “ringing” refers to the formation of a whitish or opaquering around a container containing a liquid, for example, an aqueousliquid, for example a beverage, for example, a liquid dilutioncomposition containing an emulsion or nanoemulsion. Typically, the ringforms around the perimeter of the container, typically at the surfacelevel of the liquid in the container, for example, at the neck of thecontainer. Ringing can occur over time and, if it occurs over a shortperiod of time, can be a sign of instability. Ringing typically isundesirable, particularly in the case of a liquid for human consumption,for example, a beverage. Typically, the provided concentrates and liquiddilution compositions do not exhibit ringing or are stable, withoutringing, for a period of time, for example, days, weeks, months oryears.

As used herein, “stability” refers to a desirable property of theprovided concentrates and liquid dilution compositions, for example, theability of the provided concentrates and liquid dilution compositions toremain free from one or more changes over a period of time, for example,at least or longer than 1 day, 1 week, 1 month, 1 year, or more. Forexample, a concentrate or liquid dilution composition can be describedas stable if it is formulated such that it remains free from oxidationor substantial oxidation over time, remains clear over time, remainssafe and/or desirable for human consumption over time, has a lack ofprecipitates forming over time, has a lack of ringing over time, and/ordoes not exhibit any visible phase separation over a period of time. Forexample, the concentrates and liquid dilution compositions can bedescribed as stable if they exhibit one or more of these describedcharacteristics, over time, when kept at a particular temperature, forexample, room temperature, e.g., at or about 25° C., slightly below roomtemperature, e.g., between or between about 19° C. and 25° C., atrefrigerated temperatures, e.g., at or about 4° C., or at frozentemperatures, e.g., at or about −20° C. or lower.

As used herein, “phase separation” refers to the physical separation ofa homogenous emulsion, for example, the separation of the oil and waterphases of an emulsion, into two separate visible heterogeneous layers.

As used herein, “stabilize” means to increase the stability of one ofthe provided compositions.

As used herein, “room temperature” and “ambient temperature” are used todescribe a temperature that is common in one or more enclosed spaces inwhich human beings typically are or reside. Room temperature can vary,but generally refers to temperatures between or between about 19° C. and25° C. When a composition is stored at room temperature, it should beunderstood it is generally kept at a temperature within this range orabout within this range.

As used herein, “refrigerated temperature” refers to a temperature thatis common in a refrigerator, for example, a household or restaurantrefrigerator, for example, a temperature that is cooler than roomtemperature, but typically a few degrees above the freezing point ofwater. Typically, refrigerated temperatures are between or between about0° C. and 10° C., for example, at or about 4° C. When a composition isstored at a refrigerated temperature, it should be understood that it iskept at a temperature common to household or industrial refrigerators.

As used herein, “frozen temperature” refers to a temperature around orbelow the freezing point of water, e.g., a temperature commonly used ina household freezer, for example, 0° F. or about 0° F., or −19° C. orabout −19° C. or −20° C. or about −20° C., or colder.

As used herein, “hydrophilic” and “polar” refer synonymously toingredients and/or compounds having greater solubility in aqueousliquids, for example, water, than in fats, oils and/or organic solvents(e.g., methanol, ethanol, ethyl ether, acetone and benzene).

As used herein, a “solvent” is an ingredient that can be used todissolve another ingredient. Solvents include polar and non-polarsolvents. Non-polar solvents include oils and other non-polaringredients that dissolve non-polar compounds. Typically, the non-polarsolvent included in the concentrates or liquid dilution compositionsprovided herein is an oil that is in addition to the non-polaringredient. The non-polar solvent typically is not the non-polaringredient itself, i.e., is distinct from the non-polar ingredient. Morethan one non-polar solvent can be used. Certain compounds, for example,flaxseed oil and safflower oil, can be non-polar solvents and non-polaringredients. Typically, the non-polar solvent contains one or more oils,typically oils other than the non-polar ingredient or oil(s) notcontained in the non-polar ingredient. Exemplary non-polar solventsinclude, but are not limited to, oils (in addition to the non-polaringredient), for example, vitamin E oil, flaxseed oil, CLA, borage oil,rice bran oil, D-limonene, canola oil, corn oil, MCT oil and oat oil.Other oils also can be used.

As used herein, “polar solvent” refers to a solvent that is readilymiscible with water and other polar solvents. Polar solvents arewell-known and can be assessed by measuring any parameter known to thoseof skill in the art, including dielectric constant, polarity index anddipole moment (see, e.g., Przybytek (1980) “High Purity Solvent Guide,”Burdick and Jackson Laboratories, Inc.). For example, polar solventsgenerally have high dielectric constants, such as greater than or about15, generally have high polarity indices, typically greater than orabout 3, and generally large dipole moments, for example, greater thanor about 1.4 Debye. Polar solvents include polar protic solvents andpolar aprotic solvents.

As used herein, a “polar protic solvent” is a polar solvent containing ahydrogen atom attached to an electronegative atom, such that thehydrogen has a proton-like character and/or the bond between thehydrogen and electronegative atom is polarized. Exemplary polar proticsolvents include, but are not limited to, water, alcohols, includingmonohydric, dihydric and trihydric alcohols, including, but not limitedto, methanol, ethanol, glycerin and propylene glycol.

As used herein, “monohydric alcohols” are alcohols that contain a singlehydroxyl group including, but not limited to, methanol, ethanol,propanol, isopropanol, n-butanol and t-butanol.

As used herein, “dihydric alcohols” are alcohols that contain twohydroxyl groups. Exemplary dihydric alcohols include, but are notlimited to, glycols, e.g., propylene glycol, ethylene glycol,tetraethylene glycol, triethylene glycol and trimethylene glycol.

As used herein, “trihydric alcohols” are alcohols that contain threehydroxyl groups. Exemplary trihydric alcohols include, but are notlimited to, glycerin, butane-1,2,3-triol, pentane-1,3,5-triol and2-amino-2-hydroxymethyl-propane-1,3-diol.

As used herein, “non-polar,” “lipophilic” and “lipid-soluble”synonymously refer to compounds and/or ingredients, for example,non-polar compounds and non-polar ingredients, which have greatersolubility in organic solvents (e.g., ethanol, methanol, ethyl ether,acetone and benzene), fats and oils than in aqueous liquids, forexample, water. Non-polar ingredients include drugs, hormones, vitamins,nutrients and other lipophilic compounds. Typically, non-polaringredients are poorly water-soluble, for example, water insoluble orcompounds having low water solubility. Exemplary non-polar ingredientsinclude ingredients that contain one or more non-polar compounds, forexample, lipid-soluble drugs, hormones, essential fatty acids, forexample, polyunsaturated fatty acids (PUFA), for example, omega-3 andomega-6 fatty acids, vitamins, nutrients, nutraceuticals, minerals andother compounds. Additional exemplary non-polar ingredients aredescribed herein. The provided compositions can be formulated with anynon-polar ingredient, for example, any non-polar ingredient that is orcontains a non-polar compound.

As used herein, “non-polar compound” refers to a compound that containsan active component or is active such that, when administered to asubject, for example, a human, induces or is proposed to induce adesired response, such as altering body function at the cellular,tissue, organ or other level, and/or altering the cosmetic appearance orother property, or a compound that is ingested in order to achieve adesired effect. Non-polar compounds include any synthetic or naturalnon-polar ingredient or compound, including a pharmaceutical, drug,therapeutic, nutritional supplement, herb, hormone or other ingredient.Non-polar compounds can include the non-polar compounds listed herein,as well as other pharmaceutically acceptable or food-grade activederivatives of the non-polar compounds, for example, salts, esters,amides, prodrugs, active metabolites, isomers, fragments and analogs.Non-polar compounds can include compounds proven to have a desiredeffect and also compounds thought to produce such effects, for example,compounds typically ingested for nutritional supplementation purposes.The non-polar compound can be contained in a non-polar ingredient or isthe non-polar ingredient.

As used herein, a “subject” includes an animal, typically a mammal,typically a human.

As used herein, an “additive” includes anything that one can add to afood, beverage, or other human consumable to enhance one or more of itsnutritional, pharmaceutical, dietary, health, nutraceutical, healthbenefit, energy-providing, treating, holistic, or other properties. Forexample, the additives can be oil-based additives (e.g., non-polaringredients), such as nutraceuticals; pharmaceuticals; vitamins, forexample, oil-soluble vitamins, e.g., vitamin D, vitamin E and vitamin A;minerals; fatty acids, such as essential fatty acids, for example,polyunsaturated fatty acids, e.g., omega-3 fatty acids and omega-6 fattyacids, such as alpha-linolenic acid (ALA), docosahexaenoic acid (DHA),eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), CLA, sawpalmetto extract, flaxseed oil, fish oil and algae oil; phytosterols;coenzymes, such as coenzyme Q10; and any other oil-based additives.

As used herein, “water insoluble” refers to a compound that does notdissolve when the compound is mixed with water, for example, when mixedwith water at room temperature, for example, between or between about25° C. and 50° C.

As used herein, “low water solubility” refers to a compound that has asolubility in water of less than or about 30 mg/mL, for example, whenmixed with water at room temperature, such as between or between about25° C. and 50° C. As used herein, “poorly water-soluble” can be used torefer to compounds, for example, non-polar compounds, that are waterinsoluble or have low water solubility.

As used herein, “pre-emulsion concentrate” is used to refer to theprovided compositions that contain the water-soluble vitamin Ederivative mixtures (compositions) described herein, i.e., water-solublevitamin E derivative mixtures (compositions) that contain a mixture ofmonomers and dimers of the water-soluble vitamin E derivatives, andcontain a substantial amount (compared to prior art preparations), i.e.,13% to 95%, inclusive, such as at least 13%, 20%, 25%, 29%, up to asmuch as 75%, 80%, 85%, 90%, or 95%, by weight, of the dimer form andgenerally less than 70%, 65%, 63%, 62%, 61% or 60%, or less of themonomer form; and one or more non-polar ingredients that are or containnon-polar compounds and can be diluted in aqueous media, for example, inwater, to form the provided aqueous liquid dilution compositions. Thepre-emulsion concentrates can additionally include other ingredients,such as preservatives or non-polar solvents. The pre-emulsionconcentrates typically do not contain any polar solvent, such as water.Typically, the pre-emulsion concentrates are semi-solid compositions,which typically have a waxy consistency, for example, the consistency ofa substance such as wax, for example, a lip balm, at room temperature,for example, at 25° C. or about 25° C., and become liquid at highertemperatures, for example when heated to higher temperatures, such as to125° F. or about 125° F., or to 50° C. or about 50° C. or to 60° C. orabout 60° C.

As used herein, “waxy” is used to describe compositions and materials,typically oil-soluble compositions or materials, that are similar inconsistency to one or more waxes. Pre-emulsion concentrates,particularly those with higher concentrations (greater than 25% or 30%)of the water-soluble vitamin E derivative composition described hereinhave a waxy consistency at room temperature. Compositions and compoundshaving waxy consistencies typically have melting points or meltingranges above ambient temperature (e.g., above room temperature, forexample, above 25° C. or about 25° C.), meaning they are either solid orsemi-solid (i.e., not liquid) at room temperature. Typically, waxycompositions are of relatively low viscosity a little above theirliquefying point. Exemplary of waxes that have waxy consistencies arenatural waxes, including waxes of vegetal origin, such as purcellin,shea butter, cocoa butter, Japan wax, esparto grass wax, cork wax,Guaruma wax, rice shoot wax, Ouricury wax, montan wax, sunflower wax,sugar cane wax, carnauba wax, candelilla wax; fruit-derived waxes, suchas orange wax, lemon wax, grapefruit wax and bayberry wax; waxes ofanimal origin, such as beeswax, lanolin, wool wax, spermaceti and bearfat, shellac wax; mineral waxes such as ceresine and ozokerite waxes;and synthetic waxes, including petroleum-based waxes such as paraffin,petrolatum, micro wax, polyalkylene and polyethyleneglycol waxes, e.g.polyethylene wax; waxes based on chlorinated naphthalenes, such as“Halowax”; synthetic hydrocarbon waxes.

As used herein, “liquid concentrate” and “liquid nanoemulsionconcentrate” are used synonymously to refer to the provided compositionsthat contain the water-soluble vitamin E derivative mixtures(compositions) described herein, i.e., water-soluble vitamin Ederivative mixtures (compositions) that contain a mixture of monomersand dimers of the water-soluble vitamin E derivatives, and contain asubstantial amount (compared to prior art preparations), i.e., 13% to95%, inclusive, such as least 13%, 20%, 25%, 29%, up to as much as 75%,80%, 85%, 90%, 95%, by weight, of the dimer form and generally less than70%, 65%, 63%, 62%, 61% or 60% or less of the monomer form; one or morenon-polar ingredients that are or contain one or more non-polarcompounds; a polar solvent; and optionally, additional ingredients. Theliquid concentrates are liquid at room temperature, for example, at atemperature of at or about 25° C. or between or between about 25° C. and50° C., and can be diluted in aqueous media, for example, in water, toform the provided aqueous liquid dilution compositions. Typically, theliquid concentrate is an emulsion that has a particle (droplet) size (orcan be diluted to form an aqueous liquid dilution composition having aparticle size) that is less than or about 1000 nm. For example, theparticle size can be less than or about 200 nm.

As used herein, “aqueous liquid dilution composition,” “liquid dilutioncomposition,” “dilution composition” and “liquid dilution” are usedsynonymously to refer to a composition that contains one or more of theprovided concentrates (i.e., the pre-emulsion concentrates or liquidnanoemulsion concentrates provided herein) diluted in a liquid, forexample, an aqueous medium, e.g., water. For example, the concentrateforms the dispersion phase within the aqueous liquid, which is anemulsion (e.g., nanoemulsion). The liquid dilution compositions aretypically beverages suitable for human consumption. Exemplary of liquiddilution compositions are aqueous compositions that contain theconcentrates provided herein, for example, waters, sauces, soups,syrups, soda, juice, e.g., fruit juice, milk, coffee, tea, nutritionalbeverages, sports drinks, energy drinks, vitamin-fortified beverages,flavored waters and any other beverage containing the dilutedconcentrates. It is not necessary that the aqueous liquid dilutioncompositions be completely aqueous. For example, the aqueous liquiddilution compositions can be primarily aqueous and can contain anaqueous portion, for example, an aqueous continuous phase, as well as anadditional portion, for example, a dispersion phase, such as alipophilic dispersion phase. Typically, the lipophilic dispersion phasecontains one or more lipophilic substances, for example, thewater-soluble vitamin E derivative mixtures (compositions) describedherein and one or more non-polar ingredients, for example, non-polaringredients that are or contain non-polar compounds.

As used herein, a “beverage composition” or “beverage product” refers toa composition, typically an aqueous ingestible composition, thatcontains one or more of the provided concentrates, one or morestabilizers, and a beverage base that contains a polar solvent, such aswater, a juice, a juice concentrate, a fruit juice extract or a fruitflavor. Typically, beverage compositions provided herein are providedfor direct ingestion, that is they are directly consumed by a subject,e.g., a human. Beverage compositions can be formed by dissolving thepre-emulsion concentrates and liquid nanoemulsion concentrates providedherein in an aqueous liquid, e.g., water, to form an aqueous liquiddilution composition.

As used herein, “food and beverage product” refers to a product that issuitable for human consumption. For example, “food and beverage product”can refer to a pre-emulsion concentrate or liquid nanoemulsionconcentrate that is dissolved in a solvent, typically an aqueoussolvent, e.g., water, to form a liquid dilution composition, i.e.,beverage composition or beverage product. “Food and beverage product”can also refer to the final product that is suitable for humanconsumption, such as the liquid dilution composition, i.e., beveragecomposition or beverage product.

As used herein, a “beverage base” refers to an aqueous composition towhich one or more non-polar ingredients can be added. A beverage baseincludes, but is not limited to, an aqueous composition that containsone or more of a polar solvent, typically water, a juice, such as afruit juice, a fruit juice concentrate, a fruit juice extract, a fruitflavor, a soda, a flavored soda, a carbonated water, a carbonated juiceand any combination thereof. The concentrates and/or powders providedherein a can be introduced into a beverage base (or beverage or otherfood).

As used herein, a “fruit juice,” “fruit juice concentrate,” “fruit juiceextract” or “fruit flavor” refer to fruit-based juices and flavors thatimpart taste or smell to the provided beverage compositions (products).Any juice or fruit flavor can be added to the provided beveragecompositions, including, but not limited to, plum, prune, date, currant,fig, grape, raisin, cranberry, pineapple, peach, nectarine, banana,apple, pear, guava, apricot, Saskatoon berry, blueberry, plains berry,prairie berry, mulberry, elderberry, Barbados cherry (acerola cherry),choke cherry, chocolate, vanilla, caramel, coconut, olive, raspberry,strawberry, huckleberry, loganberry, dewberry, boysenberry, kiwi,cherry, blackberry, honey dew, green tea, cucumber, quince, buckthorn,passion fruit, sloe, rowan, gooseberry, pomegranate, persimmon, mango,rhubarb, papaya, litchi, lemon, orange, lime, tangerine, mandarin andgrapefruit juices, or any combination thereof. Exemplary beveragecompositions provided herein include combinations of juices or flavorsthat impart peach mango, peach, citrus, pomegranate blueberry, tropicalberry, cherry chocolate, vanilla, cherry vanilla, chocolate blueberry,chocolate caramel, cucumber, green tea, honey-dew melon, pineapplepapaya, peach nectarine, raspberry lemonade, grape, orange tangerine,orange, lime and mixed berry flavors.

As used herein, “oil phase” refers to the portion (or phase) of acomposition, such as the concentrates and liquid dilution compositionsprovided herein, that contains one or more lipophilic ingredients and/oramphiphilic ingredients (oil phase ingredients) and is, in general, thelipid-soluble phase. In the provided emulsion compositions (e.g., thenanoemulsion concentrates and the dilution compositions), the oil phasetypically represents the dispersion phase. “Oil phase” also can be usedto refer to the liquid containing the oil phase ingredients that isgenerated, typically in an oil phase vessel, while carrying out themethods for making the liquid nanoemulsion concentrates. For example,“oil phase” can refer to the mixture of the components (oil phaseingredients) that are combined, mixed and heated, for example, in theoil phase vessel (e.g., tank), prior to mixing with the water phase.“Oil phase” can refer to the oil phase mixture that is formed after allthe ingredients are dissolved; alternatively, it can refer to theforming mixture, for example, as it is being mixed/heated.

As used herein, “oil phase ingredient(s)” refers to the components ofthe provided concentrates and liquid dilution compositions that areincluded in the oil phase in the provided methods for making theconcentrates and liquid dilution compositions. Typical oil phaseingredients include the water-soluble vitamin E derivative mixtures(compositions); non-polar ingredients, e.g., non-polar ingredients thatare or contain non-polar compounds; co-surfactants; oils, such asnon-polar solvents; preservatives; and emulsion stabilizers. Otherlipophilic and/or amphiphilic ingredients can be included in the oilphase.

As used herein, “water phase” is used to refer to the portion (or phase)of a composition, such as the concentrates and liquid dilutioncompositions provided herein, that contains one or more hydrophilicingredients and/or amphiphilic ingredients (water phase ingredients) andis, in general, the water-soluble phase. Typically, in the providedemulsion compositions, for example, the nanoemulsion concentrates andthe dilution compositions, the water phase is the continuous phase.“Water phase” also is used to refer to the liquid containing the waterphase ingredients that is generated while carrying out the methods formaking the liquid nanoemulsion concentrates. For example, “water phase”can refer to the mixture of the components (water phase ingredients)that are combined, mixed and heated, for example, in the water phasetank, prior to mixing with the oil phase. “Water phase” can refer to thewater phase mixture that is formed after all the ingredients aredissolved; alternatively, “water phase” can refer to the formingmixture, for example, as it is being mixed/heated.

As used herein, “water phase ingredient(s)” refers to the components ofthe provided concentrates and liquid dilution compositions that areincluded in the water phase (e.g., added to the water phase vessel) inthe provided methods for making the concentrates and liquid dilutioncompositions. Typical water phase ingredients include, but are notlimited to, polar solvents, typically polar protic solvents, such aswater and alcohols, typically alcohols having more than one hydroxygroup such as dihydroxy and trihydroxy alcohols, e.g., glycerol andpropylene glycol; co-surfactants; preservatives; and emulsionstabilizers. Other hydrophilic and/or amphiphilic ingredients can beincluded in the water phase.

As used herein, an “initial concentrate” is a concentrate (e.g.,pre-emulsion concentrate and/or liquid nanoemulsion concentrate) that ismade in the provided methods of formulating the provided concentrates,typically by selecting ingredients, for example, the water-solublevitamin E derivatives provided herein, non-polar ingredient(s), polarsolvent, and, optionally, other ingredients, and selecting startingconcentrations of the ingredients from an appropriate concentrationrange as described herein.

As used herein, “fatty acid” refers to straight-chain hydrocarbonmolecules with a carboxyl (—COOH) group at one end of the chain.

As used herein, “polyunsaturated fatty acid” and “PUFA” are usedsynonymously to refer to fatty acids that contain more than onecarbon-carbon double bonds in the carbon chain of the fatty acid. PUFAs,particularly essential fatty acids, are useful as dietary supplements.

As used herein, “essential fatty acids” are PUFAs that mammals,including humans, cannot synthesize using any known chemical pathway.Thus, essential fatty acids must be obtained from diet or bysupplementation. Exemplary of essential PUFA fatty acids are the omega-3(ω3; n-3) fatty acids and omega-6 (ω-6; n-6) fatty acids.

As used herein, “omega-3 (ω3; n-3) fatty acids” and “omega-3 fattyacids” are used synonymously to describe methylene-interrupted polyeneswhich have two or more cis double bonds separated by a single methylenegroup, in which the first double bond appears at the third carbon fromthe last (ω) carbon. Omega-3 fatty acids are used as dietarysupplements, for example, for disease treatment and prevention. Theprovided concentrates and liquid dilution compositions can containnon-polar ingredients that include at least one omega-3 fatty acid.Exemplary of omega-3 fatty acids are alpha-linolenic acid (α-linolenicacid; ALA) (18:3ω3) (a short-chain fatty acid); stearidonic acid(18:4ω3) (a short-chain fatty acid); eicosapentaenoic acid (EPA)(20:5ω3); docosahexaenoic acid (DHA) (22:6ω3); eicosatetraenoic acid(20:4 ω3); docosapentaenoic acid (DPA, clupanodonic acid) (22:5ω3); 16:3ω3; 24:5 ω3 and nisinic acid (24:6ω3). Longer chain omega-3 fatty acidscan be synthesized from ALA (the short-chain omega-3 fatty acid).Exemplary of non-polar ingredients containing omega-3 fatty acids arenon-polar ingredients containing DHA and/or EPA, for example, containingfish oil, krill oil and/or algae oil, for example, microalgae oil, andnon-polar ingredients containing alpha-linolenic acid (ALA), forexample, containing flaxseed oil.

As used herein, “omega-6 (ω-6; n-6) fatty acids” and “omega-6 fattyacids” are used synonymously to describe methylene-interrupted polyeneswhich have two or more cis double bonds separated by a single methylenegroup, in which the first double bond appears at the sixth carbon fromthe last (ω) carbon. The provided concentrates and liquid dilutioncompositions can contain non-polar ingredients that include at least oneomega-6 fatty acid. Exemplary of omega-6 fatty acids are linoleic acid(18:2ω6) (a short-chain fatty acid); gamma-linolenic acid (GLA)(18:3ω6); dihomo gamma linolenic acid (DGLA) (20:3ω6); eicosadienoicacid (20:2ω6); arachidonic acid (AA) (20:4ω6); docosadienoic acid(22:2ω6); adrenic acid (22:4ω6); and docosapentaenoic acid (22:5ω6).Exemplary of non-polar ingredients containing omega-6 fatty acids areingredients containing GLA, for example, borage oil. Also exemplary ofomega-6-containing non-polar ingredients are compounds containingconjugated fatty acids, for example, conjugated linoleic acid (CLA) andcompounds containing saw palmetto extract.

As used herein, “algae oil” refers to any oil derived from marinedinoflagellates in, for example, microalgae, for example,Crypthecodinium sp, particularly, Crypthecodinium cohnii. Algae oil canbe used as a non-polar ingredient, for example, as a non-polaringredient that contains a non-polar compound, in the providedconcentrates and liquid dilution compositions. The algae oil typicallycontains DHA. The algae oil can be a source of EPA.

As used herein, “fish oil” refers to any oil derived from any fish,typically a cold water fish, for example, from fish tissue, such as fromfrozen fish tissue, for example, from cod liver. Fish oil can be used asa non-polar ingredient, for example, as a non-polar ingredient thatcontains a non-polar compound, in the provided concentrates and liquiddilution compositions. The fish oil typically contains DHA. The fish oilcan also contain EPA. For example, the fish oil can contain a mixture ofDHA and EPA.

As used herein, “preservative” and “preservativer” are used synonymouslyto refer to ingredients that can improve the stability of the providedconcentrates and liquid dilution compositions. Preservatives,particularly food and beverage preservatives, are well known. Any knownpreservative can be used in the provided concentrates and liquiddilution compositions. Exemplary of the preservatives that can be usedin the provided concentrates and liquid dilution compositions areoil-soluble preservatives, such as benzyl alcohol, benzyl benzoate,methyl paraben, propyl paraben, antioxidants, for example, vitamin E,vitamin A palmitate and beta carotene. Typically, a preservative isselected that is safe for human consumption, for example, in foods andbeverages, for example, a GRAS certified and/or Kosher-certifiedpreservative, for example, benzyl alcohol.

As used herein, an “antioxidant” refers to a stabilizer or one componentof a stabilizing system that acts as an antioxidant, and that, whenadded to a beverage composition in combination with the other requiredcomponents (i.e., acid and/or bicarbonate or carbonate) yields beveragecompositions that retain one or more desired organoleptic properties,such as, but not limited to, the taste, smell, odor and/or appearance,of the beverage composition over time. Typically, antioxidants arefood-approved, e.g., edible antioxidants, for example, antioxidants thatare safe and/or approved for human consumption. Exemplary antioxidantsinclude, but are not limited to, ascorbic acid, vitamin C, ascorbate andcoenzyme Q-containing compounds, including, but not limited to, coenzymeQ10.

As used herein, an “acid” or “ingestible acid” refers to a stabilizer orone component of a stabilizing system that, when added to a beveragecomposition in combination with the other components (i.e., antioxidantand/or bicarbonate or carbonate), yields beverage compositions thatretain one or more desired organoleptic properties, such as, but notlimited to, the taste, smell, odor and/or appearance of the beveragecomposition over time. Typically, the acids are food-approved, e.g.,edible acids or ingestible acids, for example, acids that are safeand/or approved for human consumption. Exemplary acids include, but arenot limited to, citric acid, phosphoric acid, adipic acid, ascorbicacid, lactic acid, malic acid, fumaric acid, gluconic acid, succinicacid, tartaric acid and maleic acid.

As used herein, a “bicarbonate” or “carbonate” refers to a stabilizer orone component of a stabilizing system that, when added to a beveragecomposition in combination with the other components (i.e., the acidand/or antioxidant) yields beverage compositions that retain one or moredesired organoleptic properties, such as, but not limited to, the taste,smell, odor and/or appearance of the beverage composition over time.Typically, bicarbonates or carbonates are food-approved, e.g., ediblebicarbonates or carbonates, for example, bicarbonates or carbonates thatare safe and/or approved for human consumption. Exemplary bicarbonatesinclude, but are not limited to, potassium bicarbonate and sodiumbicarbonate. Exemplary carbonates include, but are not limited to,potassium carbonate, sodium carbonate, calcium carbonate, magnesiumcarbonate and zinc carbonate.

As used herein, “carbonation” or “carbonated” refers to carbon dioxidedissolved in liquid, such as a beverage base, including water. A liquid,or beverage, can be carbonated by direct addition of carbon dioxide tothe liquid or beverage.

As used herein, “emulsion stabilizer” refers to compounds that can beused to stabilize and/or emulsify and/or change the viscosity of theprovided concentrates and aqueous compositions containing the dilutedconcentrates. For example, the emulsion stabilizer can increase theviscosity of the liquid concentrate. One or more emulsion stabilizerscan be added, for example, during formulation after evaluation of aninitial concentrate, particularly if the oil and water phases of theinitial concentrate (or the aqueous liquid dilution compositionresulting from dilution of the initial concentrate) appear to beseparating. Addition of the emulsion stabilizer can prevent separationof the oil and water phases.

As used herein, a “pH adjuster” is any compound, typically an acid or abase, that is capable of changing the pH of the provided concentratesand liquid dilution compositions, for example, to reduce the pH of theconcentrates or liquid dilution composition or to increase the pH of theconcentrates or liquid dilution composition, typically without alteringother properties of the concentrates and liquid dilution composition, orwithout substantially altering other properties. pH adjusters are wellknown. Exemplary of the pH adjusters are acids, for example, citric acidand phosphoric acid, and bases.

As used herein, “flavor” is any ingredient that changes, typicallyimproves, the taste and/or smell of the provided concentrates and liquiddilution compositions, for example, the beverages.

As used herein, “natural” is used to refer to a composition, concentrateor liquid dilution composition, and/or ingredients in the composition,concentrate or liquid dilution composition, that can be found in natureand is not solely man-made. For example, benzyl alcohol is a naturalpreservative. Similarly, tocopheryl polyethylene glycol is a naturalsurfactant. The natural composition/ingredient can be GRAS and/orKosher-certified. Typically, the provided compositions, concentrates andliquid dilution compositions are natural, semi-natural and/or containone or more natural ingredients.

As used herein, “G.R.A.S.” and “GRAS” are used synonymously to refer tocompounds, compositions and ingredients that are “Generally Regarded asSafe” by the USDA and FDA for use as additives, for example, in foods,beverages and/or other substance for human consumption, such as anysubstance that meets the criteria of sections 201(s) and 409 of the U.S.Federal Food, Drug and Cosmetic Act. Typically, the compositions,concentrates and liquid dilution compositions provided herein are GRAScertified.

As used herein, “kosher” is used to refer to substances that conform toJewish Kosher dietary laws, for example, substances that do not containingredients derived from non-kosher animals or do not containingredients that were not made following kosher procedures. Typically,the compositions, concentrates and liquid dilution compositions providedherein are Kosher-certified.

As used herein, “vessel” refers to any container, for example, any tank,pot, vial, flask, cylinder or beaker that can be used to contain theingredients and/or phases of the provided concentrates and liquiddilution compositions during the methods for making the concentrates andliquid dilution compositions. The vessel can be a tank that is used tomix and/or heat one or more ingredients and/or phases of thecomposition, for example, the water phase tanks and oil phase tanks,such as during the provided scaled-up methods. The oil and the waterphases can be mixed and heated in separate tanks before combining thephases to form an emulsion. The tank can be a packaging or holding tank,which holds the provided compositions after forming the compositions,for example, the emulsions. A number of tanks are available for mixingingredients. Typically, the tanks are cleaned, for example, rinsed,soaped and/or sanitized according to known procedures prior to use andbetween uses. The tanks can be equipped with one or more mixers, forexample, a standard mixer and/or homogenizer, which are used to mix theingredients added to the tank. The tank can be equipped with a heatingand/or cooling device. For example, the tank can be a water-jacketedtank. The temperature of the water jacketed tank is controlled throughthe water-jacket, for example, to heat the contents, for example, whilemixing.

As used herein, a “water phase vessel” refers to a vessel used to mixand/or heat the water phase ingredients to generate the water phase ofthe provided compositions. The water phase vessel can be a tank. Thetank can be a water-jacketed tank, which is a tank equipped with a waterjacket that can be used to heat the contents of the tank.

As used herein, an “oil phase vessel” refers to a vessel used to mixand/or heat the oil phase ingredients to generate the oil phase of theprovided compositions. The oil phase vessel can be an oil phase tank.The tank can be a water-jacketed tank.

As used herein, “transfer device” refers to any equipment, combinationof equipment and/or system that can be used to transfer liquid, forexample, from one tank to another tank, in the provided methods formaking the concentrates and liquid dilution compositions. Exemplary ofthe transfer devices is a transfer pump and appropriate fittings, forexample, sanitary fittings, ball valves and transfer hoses, for example,food grade hoses.

As used herein a “mixer” is any piece of equipment or combination ofequipment that can be used to mix ingredients in the provided methodsfor making the concentrates and liquid dilution compositions, forexample, standard mixers and homogenizers (shears). For example, mixerscan be used to mix the ingredients of the water phase and the oil phaseand/or to mix the additional ingredients.

As used herein, “standard mixers” are mixers that are used to combine agroup of ingredients, for example, the oil phase ingredients or thewater phase ingredients, or to mix one or more ingredients with aliquid, for example, with an emulsion, for example, to mix additionalingredients with the emulsion. Standard mixers can be any mixers thatmove the material, for example, the ingredients, during heating, forexample, to promote dissolving of the ingredients.

As used herein, “homogenizer” and “shear” are used to refer to mixersthat typically have high shear, which can be used, for example, to forman emulsion, for example, to emulsify the water phase and the oil phase,in the provided methods. The homogenizers typically are capable ofhigh-shear mixing, which emulsifies the phases.

As used herein, a “cooling apparatus” is any piece of equipment orcombination of equipment that can be used with the provided methods tocool the compositions and phases and ingredients thereof, for example,during mixing and/or homogenizing, for example, to chill the mixturewhile emulsifying the oil and water phases. Exemplary of the coolingapparatuses are coolers (chillers), for example, recirculating coolerswhich can be attached, for example, to the tanks used in the providedmethods, for example, remotely or by a tank mounted in the cooler, torecirculate fluid from the tank, through the chiller and back to thetank, in order to rapidly cool and maintain the temperature of themixture during mixing. Typically, the cooling apparatus can be used tocool the liquid to between or about between 25° C. and 45° C., forexample, to at or about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44 or 45° C.

As used herein, “rapid cooling” refers to a process by which acomposition, for example, a liquid composition, for example, a formingemulsion, is cooled to a desired temperature, for example, between orbetween about 25° C. and 45° C., in less than or less than about 2hours, typically less than or less than about 1 hour, for example, lessthan or less than about 30 minutes, such as 15 minutes.

As used herein, “w/w,” “by weight,” “% by weight,” “wt %” and “weightpercent” are used synonymously to express the ratio of the mass of onecomponent of a composition compared to the mass of the entirecomposition. For example, when the amount of a particular ingredientrepresents 1%, by weight (w/w), of a concentrate, the mass of thatingredient is 1% of the mass of the entire concentrate. Similarly, whenthe amount of an ingredient is 50% (w/w) of the concentrate, the mass ofthat ingredient is 50% of the entire mass of the concentrate. Similarly,when a composition and/or a compound contains 10%, by weight, of aningredient, the mass of the ingredient is 10% of the total mass of thecomposition or compound. When a composition contains 10 wt % of aningredient, the mass of that ingredient is 10% of the mass of the entirecomposition. When only a concentration, amount, or percentage (withoutunits) is listed, it is to be understood that the concentration orpercentage is a concentration or percentage by weight.

Similarly, as used herein “v/v” and “volume percent” are usedsynonymously to express the ratio of the volume of one component of acomposition to the volume of the entire composition.

As used herein, “not more than” and “NMT” refer to a quantity that isless than or equal to the listed quantity. Similarly, “not less than”and “NLT” refer to a quantity that is greater than or equal to thelisted quantity.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to a composition containing “a non-polar ingredient”includes compositions with one or more non-polar ingredients.

As used herein, ranges and amounts can be expressed as “about” aparticular value or range. About also includes the exact amount. Hence,“about 5 grams” means “about 5 grams” and also “5 grams.” It also isunderstood that ranges expressed herein include whole numbers within theranges and fractions thereof. For example, a range of between 5 gramsand 20 grams includes whole number values such as 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 and 20 grams, and fractions within therange including, but not limited to, 5.25, 6.72, 8.5 and 11.95 grams.

As used herein, “optional” or “optionally” means that the subsequentlydescribed event or circumstance does or does not occur and that thedescription includes instances where said event or circumstance occursand instances where it does not. For example, a reaction mixture that“optionally includes a catalyst” means that the reaction mixturecontains a catalyst or it does not contain a catalyst.

As used herein, “consisting essentially of” means containing thefollowing list of ingredient(s), and not including any additionalnon-polar ingredient that is or contains a non-polar compound other thanthose listed.

As used herein, a soft gel shell is an oral dosage form foradministration of pharmaceuticals and nutraceuticals, similar tocapsules. Softgel shells are a combination of gelatin or gelatinalternative, water, opacifier and a plasticizer to lend flexibility,such as glycerin and/or sorbitol.

As used herein, a soft gel composition refers to a soft gel shell thatcontains the non-aqueous pre-gel compositions provided herein.

As used herein, a “concentrate,” particularly a “pre-gel concentrate” isa composition that generally is formulated for dilution, rather thandirect ingestion, or for direct ingestion in a small quantity, such asin a capsule. For purposes herein, a “pre-gel concentrate,” refers to acomposition that is formulated as a composition for dilution, but alsois provided in capsules, such as soft gels, for direct ingestion, wherea single capsule provides a single dosage or a fractional dosage.

As used herein, a “pre-gel concentrate” refers to a composition thatcontains in a particular volume to be encapsulated, contains a singledosage or fractional dosage of a composition containing non-polaringredients.

As used herein, fractional dosage refers to an amount that is less thata full dosage so that, when provided as a capsule, a plurality ofcapsules will be required to provide a single dosage. Typically, afractional dosage is at least 20%, 25%, 50% of a full dosage.

As used herein, “stability” of compositions, such as the pre-gelemulsions and concentrates and soft gels to remain free from one or moredeleterious changes over a period of time, for example, at least orlonger than 1 day, 1 week, 1 month, 1 year, or more. For example, aconcentrate or soft gel can be described as stable if it is formulatedsuch that it remains free from oxidation or substantial oxidation overtime, remains clear over time, remains safe and/or desirable for humanconsumption over time, does not form precipitates and remains free ofmicrobial or other contamination.

As used herein, “non-aqueous solvent” refers to any liquid other thanwater in which non-polar ingredients or compounds can be dissolved.Typically, a non-aqueous solvent is solvent that is not soluble in wateror is partially soluble in water has no or only partial solubility inwater. For purposes herein, the non-aqueous solvent is acceptable forhuman consumption. Benzyl alcohol is exemplary of such solvents.

As used herein, “excipients”, refer to any substance needed to formulatethe composition to a desired form. For example, suitable excipientsinclude but are not limited to, diluents or fillers, binders orgranulating agents or adhesives, disintegrants, lubricants,antiadherents, glidants, wetting agents, dissolution retardants orenhancers, adsorbents, buffers, chelating agents, preservatives, colors,flavors and sweeteners. Typical excipients include, but are not limitedto, starch, pregelatinized starch, maltodextrin, monohydrous dextrose,alginic acid, sorbitol and mannitol. In general, the excipient should beselected from non-toxic excipients (IIG, Inactive Ingredient Guide, orGRAS, Generally Regarded as safe, Handbook of PharmaceuticalExcipients).

As used herein, a binder is an excipient added to a composition to aidformation of a powder when the composition is dried. Non-limitingexamples of suitable binders include, but are not limited to, acacia,dextrin, starch, povidone, carboxymethylcellulose, guar gum, glucose,hydroxypropyl methylcellulose, methylcellulose, polymethacrylates,maltodextrin, hydroxyethyl cellulose, whey, disaccharides, sucrose,lactose, polysaccharides and their derivatives such as starches,cellulose or modified cellulose such as microcrystalline cellulose andcellulose ethers such as hydroxypropyl cellulose, sugar alcohols such asxylitol, sorbitol or maltitol, protein, gelatins and synthetic polymers,such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG).

As used herein, stabilizers refer to additives that aid in retainingorganoleptic properties. These include, but are not limited tocarbonate, bicarbonate and/or CO₂. Additional components, such asingestible acids and antioxidants, such as, for example, ascorbic acid,ascorbate or a coenzyme Q-containing compound, improve organolepticproperties.

B. Water-Soluble Vitamin E Derivatives

Provided herein are concentrates, compositions and beveragecompositions, such as liquid dilution compositions and aqueousbeverages, soft gel compositions and powders, that provide non-polarcompounds and contain water-soluble vitamin E derivative mixtures(compositions), such as water-soluble tocopherol-derived compositionsand tocotrienol-derived compositions. The water-soluble vitamin Ederivative mixtures (compositions) contain a relatively highconcentration, as described herein, of the dimer form of thewater-soluble vitamin E derivative. This composition is employed in thepreparation of the compositions provided herein, including the powders,soft gels, concentrates, emulsions, beverage compositions andconcentrates that contain non-polar ingredients, such as nutritionalsupplements, including water-insoluble vitamins, fatty acids,phytosterols, coenzyme Q and other such compounds, for addition tofoods, particularly aqueous beverages. Also provided are compositionsthat contain the water-soluble vitamin E derivative mixtures(compositions) with a non-polar ingredient and other optionalingredients for direct consumption without dilution.

Provided herein is a water-soluble vitamin E derivative mixture, such asa PEG derivative of vitamin E mixture, such as a TPGS mixture, that is ahigh dimer-containing mixture (as described herein) of the water-solublevitamin E derivative. These high dimer-containing water-soluble vitaminE derivative mixtures can be used in any composition in which awater-soluble vitamin E derivative is included. As described herein,these include the soft-gel compositions, the pre-gel compositions andthe powders and pre-spray emulsions. Also included are compositionsdescribed, for example, in U.S. application Ser. No. 14/207,310, andInternational PCT Application No. PCT/US14/25006, now published asUS-2014-0271593-A1 and WO 2014/151109, respectively, that includeconcentrates, e.g., the pre-emulsion concentrates and liquidnanoemulsion concentrates, that contain one or more non-polaringredients that are or contain one or more non-polar compound.

Water-soluble vitamin E derivatives can be formed by covalentlyattaching the vitamin E moiety, a hydrophobic moiety, to another moiety,such as a hydrophilic moiety, for example, a polyalkylene glycol moiety,e.g., a polyethylene glycol (PEG) moiety, via a linker. For example, thevitamin E derivative compositions can include, but are not limited to,polyalkylene glycol derivatives of tocopherol, e.g., polyethylene glycol(PEG) derivatives of tocopherol, and polyalkylene glycol derivatives oftocotrienol, e.g., polyethylene glycol (PEG) derivatives of tocotrienol,and any other derivatized water-soluble form of vitamin E, such as thosedescribed in U.S. Pub. No. 2011-0184194. The water-soluble vitamin Ederivatives include, for example, vitamin E TPGS (D-α-tocopherylpolyethylene glycol succinate), TPGS analogs, TPGS homologs and TPGSderivatives.

Polyethylene glycol derivatives of vitamin E, such as vitamin E TPGS(D-α-tocopheryl polyethylene glycol succinate), are known. Compositionsof PEG derivatives of vitamin E, for example, TPGS compositions,typically contain a mixture of monomers and dimers, where a monomer is asingle vitamin E molecule covalently joined to a water-soluble moiety,such as a polyethylene glycol, through a linker, where the water-solublemoiety, e.g., PEG, has a free, unreacted, terminal reactive group, e.g.,a free terminal hydroxyl group. A dimer is made up of two vitamin Emolecules covalently joined to a water-soluble moiety, such as apolyethylene glycol, through one or more linkers, where both ends of thewater-soluble moiety, e.g., both terminal hydroxyl groups of a PEGmoiety, have reacted with a linker that is joined to a vitamin Emolecule so that there are no free terminal reactive groups, e.g.,hydroxyl groups. For example, the monomer and dimer are formed duringthe esterification reaction between the acid moiety of vitamin Esuccinate and the terminal hydroxyl groups of a polyethylene glycol toproduce TPGS. Known TPGS compositions contain primarily TPGS monomer,e.g., between 70 wt % and 87 wt %, or higher, TPGS monomer. The monomerhas been considered the effective component and the dimer considered tobe a byproduct, thus the amounts of dimer are minimal, e.g., less than12 wt %.

In contrast, the water-soluble vitamin E derivative mixtures(compositions) employed in the concentrates and compositions providedherein are prepared so that they contain significantly more dimer, i.e.,more than 12%, particularly at least 20%, 25%, 29%, or more, generallybetween about 29-55%, 35%-55%, or more such as up to 75%, 80%, 85%, 90%or 95% dimer, and contain some monomer, i.e., less than 70 wt % monomer.For example, described herein are TPGS compositions that contain lessTPGS monomer, i.e., less than 70 wt % TPGS monomer, and more TPGS dimer,i.e., more than 12 wt % TPGS dimer, such as at least 20%, 25%, 29%, ormore, up to 75%, 80%, 85%, 90% or 95% dimer.

PEG derivatives of tocopherols or tocotrienols, e.g., TPGS, arewater-soluble and can be added to products formulated for humanconsumption, such as food and beverage products, in particular aqueousfood and beverage products, and for delivery of nutritional supplementsand drugs that have little or no solubility in aqueous compositions.They have been used, for example, to increase bioavailability of vitaminE and/or to act as a surfactant for other water-insoluble compounds, forexample, non-polar compounds.

The concentrates, powders, soft gels, and foods and beverages providedherein contain the water-soluble vitamin E derivative mixtures(compositions) that have the higher concentrations of dimer, such asTPGS compositions containing, for example, less monomer, i.e., less than70 wt %, and more dimer, i.e., more than 12 wt %.

It is shown herein that the water-soluble vitamin E derivative mixtures(compositions) described herein have advantageous properties compared tovitamin E derivative compositions that contain higher concentrations(i.e., greater than 70%) monomer. In particular, the vitamin Ederivative compositions provided herein contain at least about 13%,typically more, dimer form of the vitamin E derivative than previouspreparations, in which the amount of monomer form is maximized. It isshown herein that the vitamin E derivative compositions that containmore dimer form are more effective in solubilizing non-polar additives(non-polar compounds) in aqueous compositions than compositions thatcontain the monomer form and very little dimer form, and result incompositions and concentrates that produce liquid dilution compositions,such as aqueous beverages, that are more clear and stable thancomparable compositions produced from concentrates that contain lowamounts of dimer and higher amounts of monomer. In addition, the higherdimer-containing water-soluble vitamin E derivative mixtures(compositions) described herein permit dissolution of higherconcentrations of non-polar ingredients while retaining the clarity andstability of the resulting foods and beverages. As shown herein, higherconcentrations of non-polar ingredients can be dissolved, resulting inbeverages of greater clarity than beverages containing water-solublevitamin E derivative mixtures (compositions) that contain lowerconcentrations of dimer. In addition, across all ranges ofconcentrations of non-polar ingredients, the resulting beverages aresignificantly more clear (see Examples below). Thus, provided herein areproducts formulated for human consumption, for example, food andbeverage products, such as aqueous food and beverage products, thatcontain the water-soluble vitamin E derivative mixtures (compositions)described herein and one or more non-polar ingredients that are orcontain one or more non-polar compounds, and methods for producing suchproducts.

The concentrates containing the water-soluble vitamin E derivativemixtures (compositions) described herein can be used in aqueouscompositions, for example, aqueous food and beverage products for humanconsumption. In some instances, the concentrates can be formulated fordirect administration or direct consumption. Those compositions containlower amounts of the vitamin E derivative composition as well as amountsof the non-polar ingredient that provide a dosage or effective amountupon consumption of a single serving, such as 1-10 mL.

The food and beverage products provided herein that contain thewater-soluble vitamin E derivative mixtures with concentrations of dimerthat are greater than 12%, particularly at least 20%, 25%, 29% andhigher, contain non-polar ingredients, for example, non-polaringredients that are poorly water-soluble (e.g., have low watersolubility or are water-insoluble), that are or contain one or morenon-polar compounds. The use of the water-soluble vitamin E derivativemixtures (compositions) that contain less monomer, i.e., less than 70 wt% monomer, and more dimer, i.e., more than 12 wt % dimer, than knownwater-soluble vitamin E derivative mixtures with higher concentrationsof monomer and lower concentrations of dimer, in aqueous food andbeverage products allows for the addition of higher amounts (i.e.,concentrations) of non-polar ingredients as compared to available foodand beverage products without sacrificing clarity and stability of theresulting product. Thus, described herein are water-soluble vitamin Ederivative mixtures (compositions), such as TPGS compositions, that canbe added to food and beverage products that allow for the addition ofhigher concentrations of non-polar ingredients that result in food andbeverage products that retain desirable organoleptic properties.

1. Vitamin E

Vitamin E refers to a group of eight water-insoluble compounds thatinclude tocopherols and tocotrienols. Both structures are similar,containing a chromal ring and a 16-carbon side chain. The 16-carbon sidechain of the tocopherols is saturated, while the side chain of thetocotrienols is unsaturated, with double bonds at the 3′, 7′ and 11′positions. Each tocopherol and tocotrienol exists in the α, β, γ and δforms, differentiated by the number and position of methyl groups on thering (labeled R₁, R₂ and R₃), as shown below.

Form R₁ R₂ R₃ α Me Me Me β Me H Me γ H Me Me δ H H Me

Vitamin E is an important natural antioxidant and has been shown to haveanti-inflammatory and anti-carcinogenic activity (Yang et al. (2010)Ann. N.Y. Acad. Sci. 1203:29-34; Ju et al. (2010) Carcinogenesis31(4):533-542; Li et al. (2011) Cancer Prev. Res. (Phila.)4(3):404-413). The most common and biologically active form of vitamin Eis α-tocopherol, and is the form often referred to as vitamin E. Sincetocopherols, including α-tocopherol, cannot be synthesized in humans andanimals, they must be obtained from dietary sources. Alpha-tocopherol,the main component of vitamin E in the American diet, is most commonlyfound in wheat germ, nuts and vegetable and plant oils, such as oilsfrom soybean, corn, sesame, cottonseed, sunflower and almond.

2. Polyalkylene Glycol Derivatives of Vitamin E

The water-soluble vitamin E derivatives described herein (e.g.,water-soluble tocopherols or water-soluble tocotrienols) can includepolyalkylene glycol derivatives of vitamin E, such as polyethyleneglycol (PEG) derivatives of vitamin E, for example, PEG derivatives oftocopherols or tocotrienols. Suitable PEG derivatives of vitamin E cancontain one or more tocopherol or tocotrienol, attached to one or morePEG moiety via a linker, for example, a dicarboxylic acid linker.Exemplary dicarboxylic acid linkers include succinic acid and succinicanhydride. An exemplary water-soluble vitamin E derivative is shownschematically below:

where the line between the PEG and the linker, and the line between thelinker and the vitamin E moiety, each independently represent a covalentbond, for example, a covalent bond that forms an ester, ether, amide orthioester.

Typically, the vitamin E-PEG derivatives are made by covalentlyattaching the PEG moiety, such as by esterification, to a vitaminE-linker conjugate (e.g., a tocopherol-linker conjugate). The vitaminE-linker conjugate can be formed through esterification of the hydroxylgroup of the vitamin E moiety with a carboxylic acid group of a linker,such as a dicarboxylic acid linker. In one example, the vitamin E-linkerconjugate can be a tocopherol-linker conjugate, such as a tocopherolester, for example, tocopherol succinate. The esterification reactioncan be performed by any of a number of known methods, including thosedescribed in U.S. Pat. Nos. 2,680,749; 4,665,204; 3,538,119; and6,632,443. The resulting vitamin E-linker conjugate can then be attachedto a PEG moiety by another esterification reaction, for example, betweena carboxylic acid group of the vitamin E-linker conjugate and a hydroxylgroup of the PEG moiety, to form a vitamin E-PEG derivative.

PEG derivatives of a tocopherol-linker or tocotrienol-linker conjugatecan be made by any other method known to those of skill in the art.Various methods known in the art for producing PEG derivatives can beused to attach a PEG molecule to tocopherol-linker or tocotrienol-linkercompounds. For example, a tocopherol-linker conjugate can form acovalent bond to the PEG molecule via an amide, ether or thioether bond.For example, a tocopherol-linker conjugate that contains an amine groupcan be reacted with a PEG-NHS (N-hydroxysuccinimide) derivative to forman amide bond between the tocopherol-linker conjugate and the PEGmolecule. A tocopherol-linker conjugate that contains an amine group canbe reacted with a PEG-aldehyde derivative to form an amide bond betweenthe tocopherol-linker conjugate and the PEG molecule. In anotherexample, a tocopherol-linker conjugate that contains an carboxylic acidcan be activated to the corresponding acid halide and reacted with aPEG-SH derivative to form a thioester bond between the tocopherol-linkerconjugate and the PEG molecule.

a. Tocopherols and Tocotrienols

The tocopherols used to make the water-soluble vitamin E derivativemixtures described herein can be any natural or synthetic vitamin Etocopherol, including, but not limited to, alpha-tocopherols,beta-tocopherols, gamma-tocopherols and delta tocopherols, either inpure form or in a heterogeneous mixture of more than one form. Exemplarytocopherols are d-α-tocopherols and dl-α-tocopherols. To make thevitamin E-PEG derivative, the tocopherol typically is esterified with alinker, for example, a dicarboxylic acid, to form a tocopherol ester,which then is joined to a PEG moiety.

The tocotrienols used to make the water-soluble vitamin E derivativemixtures described herein can be any natural or synthetic vitamin Etocotrienol, including, but not limited to, alpha-tocotrienols,beta-tocotrienols, gamma-tocotrienols and delta tocotrienols, either inpure form or in a heterogeneous mixture of more than one form. Mixturesof tocopherols and tocotrienols are contemplated for use in thedescribed methods and compositions. A tocotrienol can be esterified witha linker, such as a dicarboxylic acid, before joining with a PEG moietyto form a vitamin E-PEG derivative.

b. Linkers

Typically, the water-soluble vitamin E derivatives described hereininclude a vitamin E moiety, e.g., a tocopherol or tocotrienol, attachedto a PEG moiety through a linker. The linker can be any linker that iscapable of forming a covalent bond with both the vitamin E moiety andthe PEG moiety. For example, the linker can be any linker capable offorming more than one covalent bond such as an ester bond, an amidebond, an ether bond, a thioether bond, or any combination thereof. Insome embodiments, the linker is capable of forming more than one esterbond, for example, the linker can be a dicarboxylic acid or dicarboxylicacid derivative. Exemplary dicarboxylic acids and derivatives useful aslinkers in the water-soluble vitamin E derivatives described hereininclude succinic acid, succinic anhydride, sebacic acid, dodecanedioicacid, suberic acid (i.e., octanedioic acid), azelaic acid, citraconicacid, methylcitraconic acid, itaconic acid, maleic acid, glutaric acid,glutaconic acid, fumaric acid and phthalic acid. Accordingly, exemplaryof the vitamin E-linker conjugates (i.e., tocopherol or tocotrienolattached to a linker through an ester bond) that can be furtheresterified to form the vitamin E-PEG derivatives (i.e., water-solublevitamin E derivatives) described herein are tocopheryl succinate,tocopheryl sebacate, tocopheryl dodecanodioate, tocopheryl suberate,tocopheryl azelaate, tocopheryl citraconate, tocopherylmethylcitraconate, tocopheryl itaconate, tocopheryl maleate, tocopherylglutarate, tocopheryl glutaconate, tocopheryl fumarate, tocopherylphthalate, tocotrienol succinate, tocotrienol sebacate, tocotrienoldodecanodioate, tocotrienol suberate, tocotrienol azelaate, tocotrienolcitraconate, tocotrienol methylcitraconate, tocotrienol itaconate,tocotrienol maleate, tocotrienol glutarate, tocotrienol glutaconate,tocotrienol fumarate and tocotrienol phthalate.

In other embodiments, the linker can be any compound capable of formingmore than one covalent bond, for example, a succinate ester, such asN-hydroxysuccinimide; an amino acid, such as glycine, alanine,5-aminopentanoic acid or 8-aminooctanoic acid; or an amino alcohol, suchas ethanolamine.

c. PEG Moieties

The polyalkylene moiety used to produce the water-soluble vitamin Ederivatives described herein can be any polyalkylene moiety. Exemplaryof a polyalkylene moiety is a polyethylene glycol (PEG) moiety. The PEGmoiety used in the vitamin E derivatives described herein can be any ofa plurality of known PEG moieties. Exemplary of suitable PEG moietiesare PEG moieties having varying chain lengths and varying molecularweights, such as, for example, PEG 200, PEG 500, PEG 1000 and PEG20,000, where the molecular weight of the PEG moiety is 200 Da, 500 Da,1000 Da and 20,000 Da, respectively. Typically, the number following“PEG” indicates the molecular weight, in daltons (Da), of the PEGmoiety. The PEG moiety of the water-soluble vitamin E derivativesdescribed herein typically has a molecular weight of between or aboutbetween 200 Da to 20,000 Da, for example, between or about between 200Da to 20,000 Da, 200 Da to 10,000 Da, 200 Da to 8000 Da, 200 Da to 6000Da, 200 Da to 5000 Da, 200 Da to 3000 Da, 200 Da to 1000 Da, 200 Da to800 Da, 200 Da to 600 Da, 200 Da to 400 Da, 400 Da to 20,000 Da, 400 Dato 10,000 Da, 400 Da to 8000 Da, 400 Da to 6000 Da, 400 Da to 5000 Da,400 Da to 3000 Da, 400 Da to 1000 Da, 400 Da to 800 Da, 400 Da to 600Da, 600 Da to 20,000 Da, 600 Da to 10,000 Da, 600 Da to 8000 Da, 600 Dato 6000 Da, 600 Da to 5000 Da, 600 Da to 3000 Da, 600 Da to 1000 Da, 600Da to 800 Da, 800 Da to 20,000 Da, 800 Da to 10,000 Da, 800 Da to 8000Da, 800 Da to 6000 Da, 800 Da to 5000 Da, 800 Da to 3000 Da, 800 Da to1000 Da, 1000 Da to 20,000 Da, 1000 Da to 10,000 Da, 1000 Da to 8000 Da,1000 Da to 6000 Da, 1000 Da to 5000 Da, 1000 Da to 3000 Da, 3000 Da to20,000 Da, 3000 Da to 10,000 Da, 3000 Da to 8000 Da, 3000 Da to 6000 Da,3000 Da to 5000 Da, 5000 Da to 20,000 Da, 5000 Da to 10,000 Da, 5000 Dato 8000 Da, 5000 Da to 6000 Da, 6000 Da to 20,000 Da, 6000 Da to 10,000Da, 6000 Da to 8000 Da, 8000 Da to 20,000 Da, 8000 Da to 10,000 Da, or10000 Da to 20,000 Da. For example, the PEG moiety of the water-solublevitamin E derivatives described herein can have a molecular weight of200, 300, 400, 500, 600, 800, 1000, 3000, 5000, 6000, 8000, 10,000,20,000 Da or more.

Other known PEG analogs also can be used in the water-soluble vitamin Ederivatives described herein. The PEG moieties can be selected fromamong any reactive PEG moiety, including, but not limited to, PEG-OH,PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH₂, PEG-CO₂H, and branched PEGmoieties.

Exemplary of a water-soluble vitamin E derivative having a PEG moietywith a molecular weight of 1000 Da is TPGS 1000 (i.e., D-α-tocopherylpolyethylene glycol succinate 1000).

d. Surfactant Properties

The water-soluble vitamin E derivative mixtures (compositions) describedherein, for example, the polyalkylene glycol derivatives of vitamin Edescribed herein, are surfactants. Surfactants are molecules thatcontain hydrophobic and hydrophilic portions. For example, thehydrophobic portion can be a hydrophobic tail and the hydrophilicportion can be a hydrophilic head of the surfactant molecule. Thewater-soluble vitamin E derivatives described herein can be naturalsurfactants, for example, surfactants that are G.R.A.S. certified(generally recognized as safe) by the FDA and/or Kosher certified.

Typically, surfactants aggregate in aqueous liquids, such as water, toform micelles. The hydrophilic portion(s) of the surfactant moleculesare oriented toward the outside of the micelle, in contact with theaqueous medium, while the hydrophobic portion(s) of the surfactantmolecules are oriented toward the center of the micelle. Surfactantsalso are capable of forming “inverse micelles,” which form in lipophilicmedium, the hydrophobic tails being in contact with the lipophilicmedium and the hydrophilic heads facing the center of the inversemicelle. Typically, however, the water-soluble vitamin E derivativesdescribed herein are surfactants that form micelles in aqueous medium,for example, in aqueous liquids, such as water.

The water-soluble vitamin E derivatives described herein can berepresented by an HLB (hydrophilic-lipophilic balance) value. Generally,HLB is a value derived from a semi-empirical formula, which is used toindex surfactants according to their relativehydrophobicity/hydrophilicity. An HLB value is a numericalrepresentation of the relative representation of hydrophilic groups andhydrophobic groups in a surfactant or mixture of surfactants. The weightpercent of these respective groups indicates properties of the molecularstructure. See, for example, Griffin (1949) J. Soc. Cos. Chem. 1:311.Surfactant HLB values range from 1-45, while the range for non-ionicsurfactants typically is from 1-20. The more lipophilic a surfactant is,the lower its HLB value. Conversely, the more hydrophilic a surfactantis, the higher its HLB value. Lipophilic surfactants have greatersolubility in oil and lipophilic substances, while hydrophilicsurfactants dissolve more easily in aqueous liquids. In general,surfactants with HLB values greater than 10 or greater than about 10 arecalled “hydrophilic surfactants,” while surfactants having HLB valuesless than 10 or less than about 10 are referred to as “hydrophobicsurfactants.” It should be appreciated that HLB values for a givensurfactant can vary, depending upon the empirical method used todetermine the value. Thus, HLB values of surfactants provide a roughguide for formulating compositions based on relativehydrophobicity/hydrophilicity. For example, a surfactant typically isselected from among surfactants having HLB values within a particularrange of the surfactant or co-surfactant that can be used to guideformulations. The water-soluble vitamin E derivatives described herein,such as the polyalkylene glycol derivatives of vitamin E with greaterthan 12%, 20%, 25%, or 29% dimer, are surfactants in which the vitamin Emoiety represents the hydrophobic region of the surfactant and isattached, via a linker, to a polyalkylene glycol moiety, such as apolyethylene glycol (PEG) moiety, that provides the hydrophilic portionof the surfactant. The water-soluble vitamin E derivative mixtures(compositions) described herein contain more than 12%, such as at least20%, 25% and 29%, up to 95%, 90%, 85%, 80%, or 75% of the dimer form ofthe water-soluble vitamin E derivative, such as PEG derivatives ofvitamin E. Exemplary of the water-soluble vitamin E derivatives that canbe used as surfactants are tocopherol-derived surfactants, includingpolyalkylene glycol derivatives of tocopherol, typically polyethyleneglycol (PEG) derivatives of tocopherol, such as tocopheryl polyethyleneglycol succinate (TPGS), TPGS analogs, TPGS homologs and TPGSderivatives and tocotrienol-derived surfactants, including polyalkyleneglycol derivatives of tocotrienol, typically polyethylene glycol (PEG)derivatives of tocotrienol. These are prepared as compositionscontaining the higher levels of dimers as described herein.

Exemplary of vitamin E derivatives that can be prepared for use hereinare tocopheryl polyalkylene glycol derivatives, such as tocopherylpolyethylene glycol derivatives. These include tocopheryl polyethyleneglycol succinate (TPGS), tocopheryl sebacate polyethylene glycol,tocopheryl dodecanodioate polyethylene glycol, tocopheryl suberatepolyethylene glycol, tocopheryl azelaate polyethylene glycol, tocopherylcitraconate polyethylene glycol, tocopheryl methylcitraconatepolyethylene glycol, tocopheryl itaconate polyethylene glycol,tocopheryl maleate polyethylene glycol, tocopheryl glutaratepolyethylene glycol, tocopheryl glutaconate polyethylene glycol andtocopheryl phthalate polyethylene glycol, TPGS analogs and TPGShomologs. Other tocopheryl polyethylene glycol derivatives, such asthose prepared as described in U.S. Pub. No. 2011-0184194, can be usedin the compositions, including soft gels, powders, concentrates and foodand beverage compositions described herein. These derivatives areprepared as described herein or using other methods such that theresulting compositions contain greater than 12%, such as at least 20%,25% and 29%, up to 95%, 90%, 85%, 80%, or 75% of the dimer form of thevitamin E derivative. Concentrates and beverage compositions containingsuch compounds have advantageous properties shown herein.

The water-soluble vitamin E derivatives described herein typically havean HLB value between or about between 12 and about 20, for example, 12,13, 14, 15, 16, 17, 18, 19, 20, or about 12, about 13, about 14, about15, about 16, about 17, about 18, about 19 or about 20. Exemplary ofwater-soluble vitamin E derivatives that can be used as surfactants arethe water-soluble vitamin E derivatives described herein. For example,the water-soluble vitamin E derivatives described herein, such aspolyalkylene glycol derivatives of vitamin E, have an HLB value ofbetween or about between 12 and about 20. Exemplary of a water-solublevitamin E derivate having an HLB value between or about between 12 andabout 20 is tocopheryl polyethylene glycol succinate (TPGS), such as theTPGS compositions described herein. TPGS typically has an HLB value ofbetween or about between 12 and 14 or about 13.

The following discussion describes properties and preparations of thevitamin E derivative D-α-tocopheryl polyethylene glycol succinate (TPGS)as exemplary of the water-soluble vitamin E derivatives that can beprepared in compositions with the higher levels of dimer as describedherein.

3. Tocopheryl Polyalkylene Glycol Derivatives

In its natural water-insoluble state, vitamin E, e.g., tocopherol ortocotrienol, is easily absorbed and used in humans and animals.Processing of foods and feeds by industry for long-term storage canpromote accelerated degradation of the effective vitamin E content. Tocompensate for the loss of natural vitamin E from food sources,nutritional supplements of natural or synthetic fat-soluble vitamin Ehave been developed. Not all humans and animals can sufficiently absorbthe supplements though. To address this problem, water-soluble vitamin Ederivatives have been developed that are an excellent source of vitaminE (i.e., maintain a high degree of vitamin E biological activity) inhumans with impaired vitamin E absorption, for example, in humans withmalabsorption syndromes (Traber et al. (1986) Am. J. Clin. Nutr.44:914-923). Water-soluble vitamin E derivatives have been developed forthis purpose. Tocopheryl polyethylene glycol derivatives, such as thoselisted above, are employed to produce the water-soluble vitamin Ederivative mixtures (compositions) with higher levels of dimer asdescribed herein. The water-soluble vitamin E derivative D-α-tocopherylpolyethylene glycol succinate (TPGS) is exemplary of the tocopherylpolyethylene glycol derivatives.

TPGS contains a hydrophilic (i.e., water-soluble) polyethylene glycol(PEG) chain and a lipophilic (i.e., water-insoluble) α-tocopherol head.The amphiphilic structure of TPGS, shown below, renders it much morewater-soluble than traditional vitamin E, allowing TPGS to form amicellar solution at low concentrations (0.04-0.06 mmol/L) that can beabsorbed by humans and animals in the absence of bile salts.

a. Uses

i. Nutritional Supplement

TPGS has been approved by the FDA as a water-soluble vitamin Enutritional supplement. It is a GRAS (Generally Regarded As Safe)-listedsupplement that can be taken orally at long-term doses of 13.4-16.8mg/kg/day or up to 100 mg/kg/day for people with impaired uptake. In thebody, TPGS undergoes enzymatic cleavage to deliver the lipophilicantioxidant α-tocopherol (vitamin E) to cell membranes. Cellularenzymatic hydrolysis by cytoplasmic esterases liberates freeα-tocopherol, which then localizes in the cell membrane, and throughfree radical quenching, protects the membrane from lipid peroxidationand damage.

ii. Surfactant

TPGS also is used as a non-ionic surfactant and emulsifier. Non-ionicsurface-active agents are used in oral formulations to enhance thebioavailability of water-insoluble pharmaceuticals, such as drugs,vitamins, or other biologically active compounds. TPGS is an effectiveabsorption and bioavailability enhancer, and has been approved for useas a drug solubilizer in oral, parenteral, topical, nasal, andrectal/vaginal therapies (see, e.g., Constantinides et al. (2006) Pharm.Res. 23(2):243-255; Varma et al. (2005) Eur. J. Pharm. Sci.25(4-5):445-453) and as a solubilizer for inhalation drug delivery(Fulzele et al. (2006) 23(9):2094-2106). TPGS improves thebioavailability of such water-insoluble drugs as the HIV proteaseinhibitor amprenavir (Yu et al. (1999) Pharm. Res. 16:1812-1817;Brouwers et al. (2006) J. Pharm. Sci. 95:372-383), the non-nucleosidereverse transcriptase inhibitor UC 781 (Goddeeris et al. (2008) Eur. J.Pharm. Sci. 35:104-113), cyclosporin (Sokol et al. (1991) Lancet338:212-215), paclitaxel (Zhao et al. (2010) J. Pharm. Sci.99(8):3552-3560), estradiol (Sheu et al. (2003) J. Controlled Release88:355-368), and fat-soluble vitamins such as vitamin D (Argao et al.(1992) Ped. Res. 31(2):146-150).

TPGS acts as a surfactant due to its hydrophilic polyethylene glycol(PEG) chain and its hydrophobic α-tocopherol portion. Surfactantsaggregate and form micelles in aqueous mediums such that the hydrophilicportion(s) of the surfactant molecules are oriented toward the outsideof the micelle, in contact with the aqueous medium, while thehydrophobic portion(s) of the surfactant molecules are oriented towardthe center of the micelle. In the soft gels, powders, food and beverageproducts provided herein, TPGS can act as a surfactant by formingmicelles in an aqueous medium, such as water, where the hydrophilicportion of TPGS, i.e., the polyethylene glycol (PEG) moiety, is orientedtoward the outside of the micelle, in contact with the aqueous medium,while the hydrophobic portion of TPGS, i.e., the vitamin E moiety, isoriented toward the center of the micelle, in contact with the non-polarcompound(s), which are thus contained in the center of the micelle.

The hydrophobic/hydrophilic character of a surfactant can be describedin terms of an HLB, or hydrophilic-lipophilic balance, value. The HLBvalue is a numerical representation of the molecular balance of thehydrophobic and hydrophilic portions of the surfactant, relative toother surfactants. HLB values are derived from a semi-empirical formula,where the relative weight percentages of the hydrophobic and hydrophilicgroups are indicative of surfactant properties, such as the types ofaggregates the surfactant forms, and the solubility of the surfactant(Griffin (1949) J. Soc. Cosmet. Chem. 1:311-326). Surfactant HLB valuesrange from 1-45, where the range for non-ionic surfactants typically isfrom 1-20. The more lipophilic a surfactant is, the lower its HLB value.Conversely, the more hydrophilic a surfactant is, the higher its HLBvalue. The exact HLB value for a given surfactant can vary, however,depending on the empirical method used to determine the value. Valueshave been determined for a number of surfactants (see, e.g., U.S. Pat.No. 6,267,985). TPGS is a non-ionic surfactant that, as reported, has anHLB value of approximately 13.

4. Synthesis

Scheme 1 shows the synthesis of an exemplary water-soluble vitamin Ederivative, TPGS, but any vitamin E moiety, i.e., any tocopherol ortocotrienol, can be used as the starting material and reacted with anylinker, such as those described herein, that is capable of reacting witha polyalkylene glycol moiety to form a monomer form and dimer form of awater-soluble vitamin E derivative. As shown in Scheme 1 below, TPGS canbe prepared by reacting vitamin E with succinic anhydride or succinicacid to obtain vitamin E succinate, i.e., D-α-tocopheryl succinate,followed by esterification with a polyethylene glycol molecule, toobtain TPGS (see U.S. Pat. No. 2,680,749). TPGS analogs varying in PEGchain length (e.g., TPGS 200, 238, 400, 600, 2000, 3400, 3500, 4000 and6000) have been synthesized, but the most widely used form of TPGS isTPGS 1000, which incorporates PEG 1000, a polyethylene glycol moleculewith a molecular weight of approximately 1,000 Daltons (Collnot et al.(2006) J. Controlled Release 111:35-40). TPGS 1000 is a pale yellow,waxy solid substance that is amphipathic and hydrophilic, with amolecular weight of approximately 1,513 Daltons.

TPGS compositions, as generally prepared, such as commercially availableTPGS 1000, are mixtures that contain primarily TPGS monomer (between 70%and 87% or more) and a lesser amount of TPGS dimer (less than 12%). Themonomer is considered the effective component in TPGS, while the dimeris viewed as a byproduct of the esterification reaction betweenpolyethylene glycol and vitamin E succinate. For example, commerciallyavailable TPGS, such as the TPGS 1000 available from Eastman ChemicalCompany (Kingsport, Tenn.), contains primarily TPGS monomer (˜86% ormore) and a small amount of TPGS dimer (˜11% or less) (Christiansen etal. (2011) J. Pharm. Sci. 100(5):1773-1782). TPGS synthesized accordingto standard methods, for example, the method described in U.S. Pat. No.2,680,749, results in a TPGS composition that is composed primarily ofTPGS monomer (70-87%) and a small amount of TPGS dimer (<12%) (USPharmacopeia 23 (1998) Supp. 9:4712; Scientific Panel of the EuropeanFood Safety Authority (2007) EFSA J. 490:1-20). Because the separationof TPGS monomer and TPGS dimer is difficult and because TPGS monomer isconsidered the effective component of TPGS, TPGS compositions containingprimarily TPGS dimer have not been developed (Kong et al. (2011) J.Chromatography A 1218:8664-8671). TPGS dimer, shown below, is usuallyconsidered an unwanted byproduct of the esterification reaction betweenPEG and vitamin E succinate, formed due to the equal reactivity of bothterminal hydroxyl groups of the PEG moiety.

5. Water-Soluble Vitamin E Derivative Mixtures (Compositions)

Described herein are water-soluble vitamin E derivative mixtures(compositions), for example, TPGS compositions, that contain varyingamounts of monomer and dimer, particularly compositions that containless monomer than is found in typical, known water-soluble vitamin Ederivative mixtures (compositions), for example, less than 70 wt %monomer, and more dimer, i.e., greater than 12 wt % dimer, than intypical, known water-soluble vitamin E derivative mixtures(compositions), for example, known TPGS compositions. For example, thewater-soluble vitamin E derivative mixtures (compositions) describedherein can contain between or between about 25 wt % and 69 wt % monomerand between or between about 13 wt % and 95 wt % dimer, such aswater-soluble vitamin E derivative mixtures (compositions) containingbetween or about between 40 wt % and 60 wt % monomer and between orabout between 25 wt % and 60 wt % dimer, such as 29% to 55%, 35% to 50%or 30% to 45%, dimer. Advantageous properties are exhibited bycompositions that contain at least these amounts.

In the water-soluble vitamin E derivative mixtures (compositions)described herein, the total amount of monomer as a percentage (%), byweight, of the composition (wt %) can be, e.g., between or between about25 wt % and 69 wt % monomer, inclusive, such as between or between about25% and 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and55%, 25% and 60%, 25% and 65%, 25% and 69%, 30% and 35%, 30% and 40%,30% and 45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% and 65%, 30% and69%, 35% and 40%, 35% and 45%, 35% and 50%, 35% and 55%, 35% and 60%,35% and 65%, 35% and 69%, 40% and 45%, 40% and 50%, 40% and 55%, 40% and60%, 40% and 65%, 40% and 69%, 45% and 50%, 45% and 55%, 45% and 60%,45% and 65%, 45% and 69%, 50% and 55%, 50% and 60%, 50% and 65%, 50% and69%, 55% and 60%, 55% and 65%, 55% and 69%, 60% and 65%, 60% and 69%,and 65% and 69% monomer, by weight, of the composition. Generally, thecompositions contain less than 69 wt % monomer. For example, thewater-soluble vitamin E derivative mixtures (compositions) describedherein contain at least or about at least 25%, 30%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%,53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,67%, 68%, but less than 69% (wt %), total monomer.

In the water-soluble vitamin E derivative mixtures (compositions)described herein, the total amount of dimer as a percentage (%), byweight, of the composition (wt %) can be, e.g., between or between about13 wt % and 95 wt % dimer, inclusive, such as between or between about13% and 20%, 13% and 25%, 13% and 30%, 13% and 35%, 13% and 40%, 13% and45%, 13% and 50%, 13% and 55%, 13% and 60%, 13% and 65%, 13% and 70%,13% and 75%, 13% and 80%, 13% and 85%, 13% and 90%, 13% and 95%, 20% and25%, 20% and 30%, 20% and 35%, 20% and 40%, 20% and 45%, 20% and 50%,20% and 55%, 20% and 60%, 20% and 65%, 20% and 70%, 20% and 75%, 20% and80%, 20% and 85%, 20% and 90%, 20% and 95%, 25% and 30%, 25% and 35%,25% and 40%, 25% and 45%, 25% and 50%, 25% and 55%, 25% and 60%, 25% and65%, 25% and 70%, 25% and 75%, 25% and 80%, 25% and 85%, 25% and 90%,25% and 95%, 30% and 35%, 30% and 40%, 30% and 45%, 30% and 50%, 30% and55%, 30% and 60%, 30% and 65%, 30% and 70%, 30% and 75%, 30% and 80%,30% and 85%, 30% and 90%, 30% and 95%, 35% and 40%, 35% and 45%, 35% and50%, 35% and 55%, 35% and 60%, 35% and 65%, 35% and 70%, 35% and 75%,35% and 80%, 35% and 85%, 35% and 90%, 35% and 95%, 40% and 45%, 40% and50%, 40% and 55%, 40% and 60%, 40% and 65%, 40% and 70%, 40% and 75%,40% and 80%, 40% and 85%, 40% and 90%, 40% and 95%, 45% and 50%, 45% and55%, 45% and 60%, 45% and 65%, 45% and 70%, 45% and 75%, 45% and 80%,45% and 85%, 45% and 90%, 45% and 95%, 50% and 55%, 50% and 60%, 50% and65%, 50% and 70%, 50% and 75%, 50% and 80%, 50% and 85%, 50% and 90%,50% and 95%, 55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 55% and80%, 55% and 85%, 55% and 90%, 55% and 95%, 60% and 65%, 60% and 70%,60% and 75%, 60% and 80%, 60% and 85%, 60% and 90%, 60% and 95%, 65% and70%, 65% and 75%, 65% and 80%, 65% and 85%, 65% and 90%, 65% and 95%,70% to 75%, 70% and 80%, 70% and 85%, 70% and 90%, 70% and 95%, 75% and80%, 75% and 85%, 75% and 90%, 75% and 95%, 80% and 85%, 80% and 90%,80% and 95%, 85% and 90%, 85% and 95% and 90% and 95% dimer, by weight,of the composition. Generally, the compositions contain less than 95 wt% dimer. For example, the water-soluble vitamin E derivative mixtures(compositions) described herein contain at least or about at least 13%,15%, 20%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%,37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%,51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, but less than 95% (wt %) total dimer.

The compositions described herein containing less than 70 wt % monomerand greater than 12 wt % dimer exhibit decreased turbidity values whendissolved in an aqueous solution, for example, when dissolved in water,as compared to typical, known water-soluble vitamin E derivativemixtures (compositions), i.e., water-soluble vitamin E derivativemixtures (compositions) that contain more than 70 wt % monomer and lessthan 12 wt % dimer. The compositions described herein containing lessthan 70 wt % monomer and greater than 12 wt % dimer allow for theaddition of a higher concentration of non-polar ingredients when used inthe compositions provided herein, including the powders, soft gelcompositions, aqueous food and beverage products as compared toavailable aqueous food and beverage products, while maintaining clarityand stability, for example, exhibiting decreased turbidity values.

Exemplary of the compositions described herein are TPGS compositionscontaining less than 70 wt % TPGS monomer and more than 12 wt % TPGSdimer, such as compositions containing between or about between 25 wt %and 69 wt % TPGS monomer and between or about between 13 wt % and 95 wt% TPGS dimer, such as TPGS compositions containing between or aboutbetween 40 wt % and 60 wt % TPGS monomer and between or about between 25wt % and 60% TPGS dimer, are described herein. The compositionsdescribed herein containing less than 70 wt % TPGS monomer and greaterthan 12 wt % TPGS dimer exhibit decreased turbidity values whendissolved, for example, when dissolved in water, as compared to typical,known TPGS compositions, i.e., TPGS compositions that contain more than70 wt % TPGS monomer and less than 12 wt % TPGS dimer. The TPGScompositions described herein allow for the addition of a higherconcentration of non-polar ingredients when used in aqueous food andbeverage products as compared to available aqueous food and beverageproducts, while maintaining clarity and stability, for example,exhibiting decreased turbidity values.

The water-soluble vitamin E derivative mixtures (compositions), e.g.,TPGS compositions, described herein contain a mixture of monomer anddimer, e.g., a mixture of TPGS monomer and TPGS dimer. The monomer, forexample, a TPGS monomer, can be present in an amount that is less thanwhat is typically found in known water-soluble vitamin E derivativemixtures (compositions), e.g., known TPGS compositions, i.e., less than70 wt % monomer. The dimer, for example, a TPGS dimer, can be present inan amount that is greater than what is typically found in knownwater-soluble vitamin E derivative mixtures (compositions), e.g., knownTPGS compositions, i.e., greater than 12 wt % dimer. The water-solublevitamin E derivative mixtures (compositions), such as the TPGScompositions, described herein can also contain other components, suchas, for example, unreacted PEG, unreacted vitamin E, e.g.,D-α-tocopheryl succinate, and one or more catalysts.

Methods for preparing the water-soluble vitamin E derivative mixtures(compositions), such as the TPGS compositions described herein, aredescribed herein, for example, methods of preparing water-solublevitamin E derivative compositions, such as TPGS compositions, thatcontain less than 70 wt % TPGS monomer and more than 12 wt % TPGS dimer.Existing methods for preparing derivatives of vitamin E can be employed,except that the methods are modified to produce higher concentrations ofthe dimer form by modifying reaction conditions. Such modifications canbe determined empirically if needed, such as by varying reactionparameters, such as time, temperature and reactant concentrations, toidentify conditions that favor higher levels of dimer production.

The water-soluble vitamin E derivative mixtures e.g., TPGS monomer-dimermixtures, prepared according to the methods, can contain between orabout between 25 wt % and 69 wt % monomer, for example, at or about 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68 or 69 wt % monomer and between or aboutbetween 13 wt % and 95 wt % dimer, for example, at or about 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94 or 95 wt % dimer.

Exemplary of the water-soluble vitamin E derivative mixtures(compositions) described herein that contain a mixture of monomer anddimer, for example, TPGS compositions that contain a mixture of TPGSmonomer and TPGS dimer, are compositions that contain between or aboutbetween 25 wt % and 69 wt % monomer and between or about between 13 wt %and 95 wt %, such as 29% to 55%, dimer. For example, the water-solublevitamin E derivative mixtures can contain at or about at least 39.35 wt% monomer and at or about at least 35.56 wt % dimer; at or about 40.39wt % monomer and at or about 54.90 wt % dimer; at or about 40.95 wt %monomer and at or about 53.15 wt % dimer; at or about 42.76 wt % monomerand at or about 51.10 wt % dimer; at or about 43.52 wt % monomer and ator about 49.80 wt % dimer; at or about 43.90 wt % monomer and at orabout 53.90 wt % dimer; at or about 52.92 wt % monomer and at or about33.70 wt % dimer; at or about 55.88 wt % monomer and at or about 29.27wt % dimer; at or about 57.70 wt % monomer and at or about 40.40 wt %dimer; at or about 60.00 wt % monomer and at or about 38.10 wt % dimer;and at or about 70.90 wt % monomer and at or about 28.65 wt % dimer.Thus, described herein are water-soluble vitamin E derivative mixtures(compositions), such as TPGS compositions, that contain less monomer,i.e., less than 70 wt % monomer, such as between 25 wt % and 69 wt %monomer, and more dimer, i.e., more than 12 wt % dimer, such as between13 wt % and 95% dimer, than typical commercial TPGS compositions.

The concentrates containing water-soluble vitamin E derivative mixtures,such as tocopheryl polyalkylene glycol derivative compositions,including TPGS compositions, described herein, allow for thesolubilization of higher amounts of non-polar ingredients, such asnon-polar ingredients that are or contain non-polar compounds, in foodsand beverages, particularly aqueous beverages to which the concentrateis added. Provided herein are powders, soft gel compositions, pre-gelcompositions, pre-emulsion concentrates, liquid nanoemulsionconcentrates and liquid dilution compositions, capsules, tablets andbeverage compositions that contain the high dimer-containingwater-soluble vitamin E derivative mixtures (compositions) describedherein.

For example, these concentrates allow for the addition of non-polaringredients that are or contain non-polar compounds to products suitablefor human consumption in amounts between or between about 1 wt % and 75wt %, such as between or between about 1% and 5%, 1% and 10%, 1% and15%, 1% and 20%, 1% and 25%, 1% and 30%, 1% and 35%, 1% and 40%, 1% and45%, 1% and 50%, 1% and 55%, 1% and 60%, 1% and 65%, 1% and 70%, 1% and75%, 5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and 30%, 5% and35%, 5% and 40%, 5% and 45%, 5% and 50%, 5% and 55%, 5% and 60%, 5% and65%, 5% and 70%, 5% and 75%, 10% and 15%, 10% and 20%, 10% and 25%, 10%and 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% and 50%, 10% and55%, 10% and 60%, 10% and 65%, 10% and 70%, 10% and 75%, 15% and 20%,15% and 25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% and50%, 15% and 55%, 15% and 60%, 15% and 65%, 15% and 70%, 20% and 25%,20% and 30%, 20% and 35%, 20% and 40%, 20% and 45%, 20% and 50%, 20% and55%, 20% and 60%, 20% and 65%, 20% and 70%, 20% and 75%, 25% and 30%,25% and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and 55%, 25% and60%, 25% and 65%, 25% and 70%, 25% and 75%, 30% and 35%, 30% and 40%,30% and 45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% and 65%, 30% and70%, 30% and 75%, 35% and 40%, 35% and 45%, 35% and 50%, 35% and 55%,35% and 60%, 35% and 65%, 35% and 70%, 35% and 75%, 40% and 45%, 40% and50%, 40% and 55%, 40% and 60%, 40% and 65%, 40% and 70%, 40% and 75%,45% and 50%, 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%, 45% and75%, 50% and 55%, 50% and 60%, 50% and 65%, 50% and 69%, 55% and 60%,55% and 65%, 55% and 70%, 55% and 75%, 60% and 65%, 60% and 70%, 60% and75%, 65% and 70%, 65% and 75% and 70% and 75% non-polar ingredient, byweight, of the food or beverage product. Generally, the products containless than 75 wt % non-polar ingredient. For example, the food andbeverage products containing the water-soluble vitamin E derivativemixture, including the concentrates, provided herein contain at least orabout at least 1%, 5%, 10%, 15%, 20%, 25%, 26%, 27%, 28%, 29%, 30%, 31%,32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%,60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,74%, but less than 75% (wt %) total non-polar ingredient.

C. Methods for Making Water-Soluble Vitamin E Derivatives

The water-soluble vitamin E derivative mixtures (compositions) withhigher amounts of dimer can be prepared by modification of methods thatcompositions with higher amounts of monomer and lower amounts of dimerare prepared by, appropriately varying reaction conditions to favorincreased dimer formation. Alternatively, standard known methods can beemployed and the dimers purified or partially purified and added tocompositions to increase the percentage of dimer to a desired level.

For example, for production of compositions with higher amounts of TPGSdimer, the methods employ the use of vitamin E succinate, e.g.,D-α-tocopheryl succinate, as a starting material. Methods that usevitamin E, e.g., tocopherol or tocotrienol, and succinic acid orsuccinic anhydride as the starting materials (to synthesize vitamin Esuccinate) also can be used to prepare the water-soluble vitamin Ederivative mixtures (compositions) described herein. The methods can beadapted for production of any desired water-soluble vitamin E derivativecomposition that contains the higher amounts of dimer.

As noted, these water-soluble vitamin E derivative mixtures(compositions) exhibit decreased turbidity values as compared to knownwater-soluble vitamin E derivative mixtures (compositions), such asknown TPGS compositions, when dissolved, such as, for example, whendissolved in water or other aqueous beverages. Thus, the describedmethods are advantageous over existing prior art methods of preparingTPGS compositions that exhibit high turbidity values, e.g., higher than80 NTUs, when dissolved, such as when dissolved in water.

Water-soluble vitamin E derivatives, such as TPGS, can be prepared byesterifying vitamin E succinate, for example, D-α-tocopheryl acidsuccinate, with polyethylene glycol. The resulting vitamin E TPGS has achemical formula of C₃₃O₅H₅₄(CH₂CH₂O)_(n), where “n” represents thenumber of polyethylene oxide moieties attached to the acid group of thevitamin E succinate. In an exemplary embodiment, the method includespreparing a crude water-soluble vitamin E, e.g., TPGS, composition byfirst preparing a reaction mixture containing vitamin E succinate, apolyethylene glycol (PEG), and optionally, a catalyst, in a solvent, andheating the reaction mixture to an elevated temperature to produce acrude water-soluble vitamin E, e.g., TPGS, composition containing lessTPGS monomer and more TPGS dimer than what is typically found in knownTPGS compositions, i.e., less than 70 wt % TPGS monomer and more than 12wt % TPGS dimer. The crude water-soluble vitamin E, e.g., TPGS,composition then can be purified and concentrated to obtain a purifiedwater-soluble vitamin E, e.g., TPGS, composition containing less TPGSmonomer and more TPGS dimer than what is typically found in known TPGScompositions, i.e., less than 70 wt % TPGS monomer and more than 12 wt %TPGS dimer. Any purification process known in the art can be used topurify the reaction product.

1. Reaction Mixture

The methods include preparing a crude water-soluble vitamin E derivativemixture, such as a crude TPGS composition, by esterifying vitamin Esuccinate with polyethylene glycol in a solvent. The esterificationprocedure can be promoted by a catalyst, for example, an esterificationcatalyst. In the methods, the crude composition can be prepared from areaction mixture containing vitamin E succinate, a polyethylene glycol(PEG), a solvent, and optionally, a catalyst. The components of thereaction mixture can be added in any order. In an exemplary embodiment,the polyethylene glycol is dissolved in the solvent before the additionof vitamin E succinate and the catalyst.

The methods produce a crude water-soluble vitamin E derivative mixture,such as a crude TPGS composition, that contains less TPGS monomer andmore TPGS dimer than what is typically found in known TPGS compositions,i.e., less than 70 wt % TPGS monomer and more than 12 wt % TPGS dimer.In some instances, the crude TPGS composition contains between orbetween about 25 wt % and 69 wt % TPGS monomer and between or betweenabout 13 wt % and 95 wt % TPGS dimer, such as between or between about40 wt % and 60 wt % TPGS monomer and between or between about 25 wt %and 60 wt % TPGS dimer.

a. Vitamin E Succinate

The reaction mixtures of the methods contain vitamin E succinate, forexample, D-α-tocopheryl succinate. Vitamin E succinate can be purchasedfrom suppliers such as Sigma-Aldrich (St. Louis, Mo.), Parchem (NewRochelle, N.Y.), Fisher Scientific (Fair Lawn, N.J.), and VWRInternational (Radnor, Pa.), or can be synthesized according to methodsknown to those of skill in the art. Typically, vitamin E succinate canbe synthesized by reacting vitamin E (i.e., D-α-tocopherol) withsuccinic anhydride in a solvent (e.g., toluene) in the presence of abase (e.g., triethylamine) (see, for example, U.S. Patent Pub. Nos.2011/0130562 and 2011/0184194; Lipshutz et al. (2011) J. Org. Chem.76(11):4379-4391; Gelo-Pujic et al. (2008) Int. J. Cosmet. Sci.30(3):195-204; and Vraka et al. (2006) Bioorg. Med. Chem.14(8):2684-2696).

In the methods, the total amount of vitamin E succinate in the reactionmixture as a percentage (%), by weight, of the reaction mixture (wt %)can be, e.g., from at or about 0.1% to at or about 15%, such as 0.1% to1%, 0.1% to 3%, 0.1% to 5%, 0.1% to 10%, 0.1% to 15%, 0.5% to 1%, 0.5%to 3%, 0.5% to 5%, 0.5% to 10%, 0.5% to 15%, 1% to 3%, 1% to 5%, 1% to10%, 1% to 15%, 3% to 5%, 3% to 10%, 3% to 15%, 5% to 10%, 5% to 15%, or10% to 15%, by weight, of the reaction mixture. Generally, the reactionmixtures contain less than 15 wt % vitamin E succinate. For example, thereaction mixtures described herein contain up to at or about 1%, 2%, 3%,4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% vitamin Esuccinate. Generally, the reaction mixtures described herein containless than 15% (wt %) total vitamin E succinate.

b. Polyethylene Glycol

In the methods, the reaction mixtures include any polyethylene glycolthat can react with the acid moiety of vitamin E succinate to form anester. The polyethylene glycol can include, for example, anypolyethylene glycol that gives the desired molecular weight of thewater-soluble vitamin E compound, the desired polyethylene glycol chainlength of the water-soluble vitamin E compound or the desired amount ofwater-soluble vitamin E water-solubility. The polyethylene glycol in thereaction mixtures of the methods can include, for example, anypolyethylene glycol that is capable of forming an ester when reactedwith vitamin E succinate to produce a vitamin E derivative that iswater-soluble. For example, the polyethylene glycol can include PEG-OH,PEG-SH, PEG-NH₂ and branched PEGs. Typically, the polyethylene glycol isPEG-OH. The resulting water-soluble vitamin E product, for example,TPGS, formed by the reaction between vitamin E succinate and apolyethylene glycol contains at least polyethylene glycol esters ofvitamin E succinate. The esters can be a mixture of esters, such as amixture of TPGS monomer and TPGS dimer.

The polyethylene glycols in the reaction mixtures of the methods can beany molecular weight, for example, any molecular weight that rendersvitamin E succinate water-soluble after esterification with thepolyethylene glycol (i.e., the resulting TPGS is water-soluble). Suchpolyethylene glycols are known in the art and can be purchased fromsuppliers such as Sigma-Aldrich (St. Louis, Mo.), Fisher Scientific(Fair Lawn, N.J.), and VWR International (Radnor, Pa.). The polyethyleneglycol can be added to the reaction mixture by any method suitable fortransferring the PEG to the reaction mixture. For example, the PEG canbe transferred to the reaction mixture in molten form.

Suitable polyethylene glycols for use in the methods includepolyethylene glycols having an average molecular weight ranging frombetween or between about 100 Daltons (Da) and 20,000 Da. For example,the average molecular weight can be between or between about 200 Da and10,000 Da, or 400 Da and 5,000 Da, or 500 Da and 1500 Da, or 750 Da and1200 Da, or 1000 Da and 2,500 Da. Generally, the molecular weight of thepolyethylene glycol is less than 20,000 Da. For example, the averagemolecular weight of the polyethylene glycol used in the reactionmixtures described herein can be or can be about 100, 200, 238, 300,400, 500, 600, 750, 800, 1000, 1200, 1500, 2000, 2500, 3000, 3400, 3500,4000, 6000, 8000, 10,000, or 12,000 Da, but less than 20,000 Da.

Exemplary polyethylene glycols include PEG 100 (where 100 represents thePEG chain molecular weight), PEG 200, PEG 238, PEG 300, PEG 400, PEG500, PEG 600, PEG 750, PEG 800, PEG 1000, PEG 1200, PEG 1500, PEG 2000,PEG 2500, PEG 3000, PEG 3400, PEG 3500, PEG 4000, PEG 6000, PEG 8000,PEG 10,000, PEG 12,000 or PEG 20,000. Any other suitable polyethyleneglycol known to those of skill in the art also can be used in themethods. In some embodiments described herein, the polyethylene glycolis PEG 1000.

In the methods, the total amount of PEG in the reaction mixture as apercentage (%), by weight, of the reaction mixture (wt %) can be, e.g.,from at or about 1% to at or about 50%, such as 1% to 5%, 5% to 10%, 5%to 15%, 5% to 20%, 5% to 25%, 5% to 30%, 5% to 35%, 5% to 40%, 5% to45%, 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to40%, 10% to 45%, 10% to 50%, 15% to 20%, 15% to 25%, 15% to 30%, 15% to35%, 15% to 40%, 15% to 45%, 15% to 50%, 20% to 25%, 20% to 30%, 20% to40%, 20% to 50%, 25% to 50%, or 30% to 50%, by weight, of the reactionmixture. Generally, the reaction mixtures contain less than 50 wt % PEGFor example, the reaction mixtures described herein contain at least orabout at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%,14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%,28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%,42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, but less than 50% (wt %) totalPEG

c. Catalyst

The reaction mixtures of the methods can optionally contain a catalyst.Suitable catalysts include those catalysts that can be used to promotethe esterification reaction between the PEG and the acid moiety ofvitamin E succinate. Exemplary catalysts include acidic catalysts, suchas p-toluenesulfonic acid, oxalic acid, hydrochloric acid,trichloroacetic acid, and any other known catalyst that can promoteesterification.

In the reaction mixtures of the methods, the total amount of catalyst,as a percentage (%), by weight, of the reaction mixture (wt %) can be,e.g., from at or about 0% to at or about 15%, such as 0.01% to 0.05%,0.01% to 0.1%, 0.01% to 0.5%, 0.01% to 0.75%, 0.01% to 1%, 0.01% to 3%,0.01% to 5%, 0.01% to 10%, 0.01% to 15%, 0.05% to 0.1%, 0.05% to 0.5%,0.05% to 0.75%, 0.05% to 1%, 0.05% to 3%, 0.05% to 5%, 0.05% to 10%,0.05% to 15%, 0.1% to 0.5%, 0.1% to 0.75%, 0.1% to 1%, 0.1% to 3%, 0.1%to 5%, 0.1% to 10%, 0.1% to 15%, 0.5% to 0.75%, 0.5% to 1%, 0.5% to 3%,0.5% to 5%, 0.5% to 10%, 0.5% to 15%, 1% to 3%, 1% to 5%, 1% to 10%, 1%to 15%, 3% to 5%, 3% to 10%, 3% to 15%, 5% to 10%, 5% to 15%, 10% to15%, by weight, of the reaction mixture. Generally, the reactionmixtures contain less than 15 wt % catalyst. For example, the reactionmixtures described herein can contain up to at or about 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% catalyst, based onthe weight of the reaction mixture.

d. Solvent

The reaction mixtures of the methods include a solvent or combination ofsolvents. Suitable solvents include those that do not prevent theesterification reaction between the PEG and acid moiety of vitamin Esuccinate from taking place. For example, the solvent or combination ofsolvents can be aprotic solvents.

Suitable solvents used in the methods include solvents that are inert tothe reaction and are aprotic, for example, solvents that lack an acidichydrogen, such as toluene, xylenes, ethers such as tetrahydrofuran(THF), diethyl ether and dioxane, ethyl acetate, acetone,dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile, methylethyl ketone (MEK), methyl isobutyl ketone (MIBK), dimethyl sulfoxide(DMSO), ethyleneglycol dimethylether, hexanes, cyclohexane, pentane,cyclopentane and any combination thereof. An exemplary solvent used inthe reaction mixtures of the methods is toluene.

In the reaction mixtures of the methods, the total amount of solvent asa percentage (%), by weight, of the reaction mixture (wt %) can be,e.g., from at or about 60% to at or about 95%, such as 60% to 65%, 60%to 70%, 60% to 75%, 60% to 80%, 60% to 85%, 60% to 90%, 60% to 95%, 65%to 70%, 65% to 75%, 65% to 80%, 65% to 85%, 65% to 90%, 65% to 95%, 70%to 75%, 70% to 80%, 70% to 85%, 70% to 90%, 70% to 95%, 75% to 80%, 75%to 85%, 75% to 90%, 75% to 95%, 80% to 85%, 80% to 90%, 80% to 95%, 85%to 90%, 85% to 95% and 90% to 95%, by weight, of the reaction mixture.Generally, the reaction mixtures contain less than 95 wt % solvent. Forexample, the reaction mixtures can contain at least or about at least60%, 65%, 70%, 75%, 80%, 85%, 90%, but less than 95% (wt %) totalsolvent.

e. Exemplary Reaction Mixtures

Exemplary reaction mixtures that can be used in the methods toultimately produce a water-soluble vitamin E derivative mixture, forexample, a TPGS composition, that contains less TPGS monomer and moreTPGS dimer than what is typically manufactured, i.e., less than 70 wt %TPGS monomer and more than 12 wt % TPGS dimer, are described. They areexemplified with TPGS, but similar reaction mixtures can be prepared andreactions performed to produce tocopherol sebacate polyethylene glycol,tocopherol dodecanodioate polyethylene glycol, tocopherol suberatepolyethylene glycol, tocopherol azelaate polyethylene glycol, tocopherolcitraconate polyethylene glycol, tocopherol methylcitraconatepolyethylene glycol, tocopherol itaconate polyethylene glycol,tocopherol maleate polyethylene glycol, tocopherol glutaratepolyethylene glycol, tocopherol glutaconate polyethylene glycol andtocopherol phthalate polyethylene glycol, TPGS analogs and TPGShomologs.

The reaction mixtures exemplified herein include vitamin E succinate, apolyethylene glycol, a solvent, and optionally, a catalyst. Exemplary ofsuch reaction mixtures contain from at or about 0.1 wt % to at or about15 wt % of vitamin E succinate; a polyethylene glycol, in an amount fromat or about 1 wt % to at or about 50 wt %; a catalyst, in an amount fromat or about 0.01 wt % to at or about 15 wt %; and from at or about 60%to at or about 95% of a solvent.

In some embodiments, the polyethylene glycol can be a polyethyleneglycol with a molecular weight of around 1000 Da, for example, PEG 1000.For example, the exemplary reaction mixtures described herein cancontain from at or about 0.1 wt % to at or about 15 wt % of vitamin Esuccinate; from at or about 1 wt % to at or about 50 wt % of apolyethylene glycol, for example, PEG 1000; from at or about 0.01 wt %to at or about 15 wt % of a catalyst, for example, p-toluenesulfonicacid; and from at or about 60% to at or about 95% of a solvent, forexample, toluene.

2. Exemplary Methods

The methods include preparing a reaction mixture containing vitamin Esuccinate, a polyethylene glycol and optionally, a catalyst, in asolvent; heating the reaction mixture to a temperature equal to orhigher than the boiling point of the solvent to form a crudewater-soluble vitamin E derivative mixture; processing the reactionmixture to obtain the crude water-soluble vitamin E derivative mixture;and purifying the crude water-soluble vitamin E derivative mixture toobtain a purified water-soluble vitamin E derivative mixture. Inparticular, the methods use the exemplary reaction mixtures describedabove. The methods to synthesize water-soluble vitamin E derivativemixtures described herein result in water-soluble vitamin E derivativemixtures, such as TPGS compositions, that are less turbid than knownwater-soluble vitamin E derivative mixtures, i.e., known compositionsthat contain more than 70% TPGS monomer and less than 12% TPGS dimer,when diluted in an aqueous medium, e.g., water.

The following methods are exemplary only and provide a platform fromwhich adjustments can be made. It is understood that changes can be madeto the steps of the method and to the reaction components whileretaining some if not all of the desirable properties of the method.Further changes can be made by adding or altering steps or components ofeach step. For example, the order in which the steps are performed canbe changed.

a. Preparation of a Crude Water-Soluble Vitamin E Derivative Mixture

Exemplary of the methods is preparation of a high dimer-containingmixture of TPGS. The methods can be employed to produce highdimer-containing mixtures of any vitamin E derivative, including PEGderivatives of vitamin E. Exemplary of the methods is a method ofpreparing a crude water-soluble vitamin E derivative mixture, forexample, a crude TPGS composition, by providing a reaction mixturecontaining vitamin E succinate, e.g. D-α-tocopheryl succinate, apolyethylene glycol, e.g., PEG 1000, a catalyst, e.g., p-toluenesulfonicacid, and a solvent, e.g., toluene, heating the reaction mixture to atemperature of at least or about at least 110° C. and maintaining theelevated temperature for a period of up to at or about 6.5 hours beforecooling, for example, to room temperature, i.e., at or about 20° C., andwashing the reaction mixture with an aqueous solution of a weak base,e.g., a 10% aqueous solution of sodium bicarbonate.

A crude water-soluble vitamin E derivative mixture is prepared byproviding a reaction mixture containing vitamin E succinate, apolyethylene glycol and optionally, a catalyst, in a solvent and heatingthe reaction mixture from room temperature, i.e., at or about 20° C., toan elevated temperature, and maintaining the elevated temperature for aperiod of time until a crude water-soluble vitamin E derivative mixture,for example, a crude TPGS composition, is formed that contains thedesired amounts of TPGS monomer and TPGS dimer. The elevated temperaturecan be any temperature in the range of from 30° C. to about 300° C.,generally between 80° C. and 250° C., such as between 100° C. and 200°C. The elevated temperature can be, for example, the boiling point ofthe solvent in the reaction mixture. A typical heating schedule can beheating the reaction mixture to a temperature of at least or about atleast 110° C. with stirring, and once achieved, the elevatedtemperature, e.g., at least or about at least 110° C., is maintained fora total time of up to at or about 6.5 hours with stirring. Other heatingtemperatures and times can be used depending on the substrates, solventand formation of the desired crude water-soluble vitamin E derivativemixture. For example, the total time the elevated temperature ismaintained can be at least at or about 1 hour, at least at or about 1.5hours, at least at or about 2 hours, at least at or about 2.5 hours, atleast at or about 3 hours, at least at or about 3.5 hours, at least ator about 4 hours, at least at or about 4.5 hours, at least at or about 5hours, at least at or about 5.5 hours, at least at or about 6 hours, orat least at or about 6.5 hours, or longer, before cooling.

After the elevated temperature has been maintained for the desiredamount of time, e.g., the amount of time required to produce the desiredamounts of TPGS monomer and TPGS dimer, the reaction mixture can becooled to a temperature lower than the elevated temperature. Forexample, the reaction mixture can be cooled to room temperature, i.e.,at or about 20° C., after heating at an elevated temperature for thedesired amount of time. The reaction mixture can be heated to at leastor about at least 110° C. for a total time of about 6.5 hours beforecooling, e.g., to room temperature (i.e., at or about 20° C.), dependingon the substrates, solvent and formation of the crude water-solublevitamin E derivative mixture, for example, a crude TPGS composition,resulting in the desired amounts of TPGS monomer and TPGS dimer. One ofskill in the art can perform the methods and, if necessary, empiricallydetermine the appropriate reaction duration to produce the desired ratioof dimer to monomer, based on the formation of the desired amounts ofTPGS monomer and TPGS dimer.

In the methods, the reaction mixture can be heated from room temperature(i.e., at or about 20° C.) to an elevated temperature of at least at orabout 30° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., 100° C.,105° C., 110° C., 115° C., 120° C., 125° C., 130° C., 140° C., 150° C.,155° C., 160° C., 165° C., 170° C., 175° C., 180° C., 185° C., 190° C.,195° C., 200° C., 205° C., 210° C., 215° C., 220° C., 225° C., 230° C.,235° C., 240° C., 245° C., 250° C., 255° C., 260° C., 265° C., 270° C.,275° C., 280° C., 285° C., 290° C., 295° C., 300° C., or higher. Thereaction mixture can be maintained at a temperature elevated from roomtemperature for at least at or about 1 hour, 1.5 hours, 2 hours, 2.5hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6hours, 6.5 hours, or longer before cooling. In an exemplary method, thereaction mixture can be maintained at an elevated temperature for up toat or about 6.5 hours before cooling, e.g., to room temperature, i.e.,at or about 20° C. The particular conditions depend upon the particularvitamin E derivative and the amount of monomer and dimer desired.

The amount of time that the reaction mixture is maintained at thetemperature elevated from room temperature, for example, between orabout between 30° C. and 300° C., such as the boiling point of thesolvent in the reaction mixture, can be determined by monitoring theprogress of reaction during heating. For example, the reaction mixturecan be monitored during heating to determine the amounts of TPGS monomerand TPGS dimer present in the reaction mixture. The heating can then beterminated when the desired amounts of TPGS monomer and TPGS dimer areformed. The monitoring can be done by any method of monitoring areaction known to those of skill in the art, such as by chromatography,spectroscopy or spectrometry. For example, the reaction can be monitoredby thin layer chromatography (TLC), high performance liquidchromatography (HPLC), infrared spectroscopy (IR), Fourier transforminfrared spectroscopy (FTIR), mass spectrometry (MS), nuclear magneticresonance (NMR) spectroscopy, or any combination thereof. In someembodiments of the methods, the reaction progress is monitored by TLC.In other embodiments, the reaction progress is monitored by HPLC. In yetother embodiments, the reaction progress is monitored by both TLC andHPLC. One of skill in the art, if necessary, can determine particularparameters empirically, such as appropriate reaction duration, based onmonitoring the formation of the desired amounts of vitamin E derivativemonomer and dimer, such as TPGS monomer and TPGS dimer.

The reaction mixture of the methods can be heated to an elevatedtemperature under an inert gas atmosphere, such as a nitrogen gas orargon gas atmosphere, or under air. The reaction mixture of the methodscan be heated to an elevated temperature at atmospheric pressure or atan elevated pressure, i.e., a pressure higher than atmospheric pressure.The elevated pressure can be achieved, e.g., by performing the reactionin a closed vessel or in a vented vessel.

The progress of the reaction can be terminated after heating for thedesired amount of time, for example, up to at or about 6.5 hours, bycooling the reaction mixture, for example, to room temperature, i.e., ator about 20° C. After cooling, such as cooling to room temperature,i.e., at or about 20° C., the reaction mixture can be washed with anaqueous solution. The aqueous solution can be an aqueous solution ofbase, such as a weak base, i.e., bases that do not fully ionize in anaqueous solution. Suitable weak bases include, for example, carbonatesor bicarbonates, e.g., sodium carbonate, sodium bicarbonate, potassiumcarbonate and potassium bicarbonate; amines, ammonias or ammoniums,e.g., methyl amine, methyl ethyl amine, dimethyl amine, aniline,ammonia, trimethyl ammonia and ammonium hydroxide; and pyridine. Forexample, the aqueous solution of base can be an aqueous solution ofsodium bicarbonate. Suitable aqueous solutions of the weak base includesolutions that contain, e.g., 1% to 20% weak base, such as at least orabout 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%,7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%,13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%,19.5%, 20%, or more, weak base. For example, the aqueous solution can bean aqueous solution containing at or about 10% sodium bicarbonate. Afterthe aqueous solution of a weak base has been added to the reactionmixture, the aqueous solution can be separated from the reactionmixture, such as by allowing the reaction mixture and aqueous solutionof weak base to separate into layers, and removed. In some embodiments,the reaction mixture and aqueous solution of weak base can be stirredfor a period of time before separating. For example, the reactionmixture and aqueous solution can be stirred for 1 minute, 2 minutes, 3minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9minutes, 10 minutes, 15 minutes, 20 minutes, or more, before allowingthe reaction mixture and aqueous solution of weak base to separate intolayers.

b. Processing the Reaction Mixture to Obtain a Crude Water-SolubleVitamin E Derivative Mixture

After preparing the reaction mixture, the reaction mixture can befurther processed in order to obtain a crude water-soluble vitamin Emixture, for example, a crude TPGS composition that contains less TPGSmonomer, i.e., less than 70 wt %, and more TPGS dimer, i.e., more than12 wt %, than known water-soluble vitamin E derivative mixtures. Thefurther processing can be performed to remove impurities from thereaction mixture before obtaining the crude water-soluble vitamin Ederivative mixture. The further processing can be performed in order toisolate the crude water-soluble vitamin E derivative mixture from thereaction mixture. For example, the reaction mixture can be furtherprocessed by treating the reaction mixture with an adsorbent, such asactivated charcoal (i.e., activated carbon). Activated charcoal can beused as a decolorizer and to remove impurities by chemical adsorption.Any activated charcoal known to those of skill in the art can be used totreat the reaction mixture. Such activated charcoal is available fromcommercial sources under such trade names as Calgon-Type CPG®, TypePCB®, Type SGL®, Type CAL®, and Type OL®.

Further processing of the reaction mixture, for example, treating thereaction mixture with activated charcoal, can take place for a period oftime of from at or about 0.5 hours to at or about 5 hours, or longer ifrequired. For example, treating the reaction mixture with activatedcharcoal can take place for at least or about at least 0.5 hours, 1hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, or longer. Thefurther processing, for example, treating the reaction mixture withactivated charcoal, can be done at any temperature of from at or aboutroom temperature, i.e., at or about 20° C., to a temperature elevatedfrom room temperature. For example, the temperature of the process,e.g., activated charcoal treatment, can be at or about 20° C., 30° C.,40° C., 50° C., 55° C., 60° C., 70° C., 80° C., 90° C., or 100° C., orany temperature between 20° C. and 100° C., such as between or aboutbetween 55° C. and 60° C. The treatment temperatures and times can bevaried depending on the reaction mixture, the solvent, and theimpurities present in the reaction mixture. In an exemplary process,such as an activated charcoal treatment process, the reaction mixturecan be treated, e.g., with activate charcoal, for at least or about atleast 1 hour at a temperature of between or about between 55° C. and 60°C., before cooling.

In the methods, the reaction mixture can be filtered and washed aftercooling, such as cooling to room temperature, i.e., at or about 20° C.,after further processing, such as after treating the reaction mixturewith activated charcoal. The reaction mixture can be filtered andwashed, for example, to remove the activated charcoal from the reactionmixture. For example, the reaction mixture can be filtered through afilter aid, such as diatomaceous earth. Suitable filter aids for use inthe methods include, for example, those sold under the trademarkCelite®, such as those sold under the trademark Hyflo®. After filteringthrough a filter aid, such as diatomaceous earth, the reaction mixturecan be washed, for example, with the same solvent used in the reactionmixture. In an exemplary embodiment, after further processing, e.g.,treatment with activated charcoal, and cooling, e.g., to roomtemperature, i.e., at or about 20° C., the reaction mixture is filteredthrough diatomaceous earth, e.g., Hyflo® filter aid, and washed withsolvent, e.g., toluene.

In the methods, the reaction mixture can be further processed in orderto isolate the crude water-soluble vitamin E derivative mixture from thereaction mixture. For example, the reaction mixture can be furtherprocessed by removing the solvent from the reaction mixture, i.e.,concentrating the reaction mixture, in order to obtain a crudewater-soluble vitamin E derivative mixture. Any method of removing asolvent from a reaction mixture known to those of skill in the art canbe used, including, for example, vacuum distillation, rotary evaporationand filtration. Removing the solvent from the reaction mixture can bedone at any temperature, for example at room temperature, i.e., 20° C.,or at a temperature elevated from room temperature. For example, thesolvent can be removed at a temperature of at or about 20° C., 30° C.,40° C., 50° C., 55° C., 60° C., 70° C., 80° C., or 90° C., but below orabout below 100° C., such as below or about below 60° C. In an exemplaryembodiment, the solvent can be removed from the reaction mixture bydistillation, e.g., vacuum distillation, at a temperature elevated fromroom temperature, i.e., at or about 20° C., but below or about below 60°C.

Further processing of the reaction mixture of the methods can includefurther processing by treating the reaction mixture to remove impuritiesfrom the reaction mixture, such as by treating the reaction mixture withactivated charcoal. Further processing of the reaction mixture of themethods can include further processing by removing the solvent from thereaction mixture, such as by removing the solvent by vacuumdistillation. The further processing can include treating the reactionmixture with activated charcoal or removing the solvent from thereaction mixture or both. In an exemplary method, the further processingof the reaction mixture includes removing the impurities from thereaction mixture, e.g., treating the reaction mixture with activatedcharcoal, and removing the solvent from the reaction mixture, e.g.,removing the solvent by vacuum distillation, in order to obtain a crudewater-soluble vitamin E derivative mixture, for example, a crude TPGScomposition, containing less TPGS monomer, i.e., less than 70 wt %, andmore TPGS dimer, i.e., more than 12 wt %, than in known TPGScompositions.

c. Purification of the Crude Water-Soluble Vitamin E Derivative Mixtureto Obtain a Purified High Dimer-Containing Water-Soluble Vitamin EDerivative Mixture

The crude water-soluble vitamin E derivative mixture obtained afterfurther processing can be further purified in order to obtain a purifiedhigh dimer-containing water-soluble vitamin E derivative mixture. Forexample, the purified water-soluble vitamin E derivative mixture can bea PEG derivative of vitamin E, such as TPGS, PTS, PTD and other TPGSanalogs and PEG derivatives of vitamin E, mixture. The mixture containsless TPGS monomer, i.e., less than 70 wt %, and more TPGS dimer, i.e.,more than 12, 19, 24, 29 wt % dimer. The purification process removesimpurities from the crude water-soluble vitamin E derivative mixture,such as impurities that were not removed by further processing of thereaction mixture. For example, the crude water-soluble vitamin Ederivative mixture can be purified by performing one or more wash, i.e.,extraction, steps. The wash can be performed using more than onesolvent, such as more than one organic solvent, for example, two organicsolvents that are not miscible with each other. For example, in themethods, the crude water-soluble vitamin E derivative mixture can bedissolved in a first solvent, for example, a polar solvent, such as analcohol, and can be washed with a second solvent, for example, anon-polar solvent, such as a hydrocarbon solvent that is not misciblewith the first solvent. The purification process, e.g., the wash, can beperformed one time, two times, three times, four times, or more,depending on the desired purity level of the water-soluble vitamin Ederivative mixture and the amount of impurities present. For example,the purification process, e.g., the wash, can be performed one or moretimes on the crude water-soluble vitamin E derivative mixture, e.g.,after the crude water-soluble vitamin E derivative mixture is obtainedafter processing. In an exemplary method, the purification process canbe performed three or more times on the crude water-soluble vitamin Ederivative mixture after the further processing is complete.

The purification process, i.e., the wash, can be performed by dissolvingthe crude water-soluble vitamin E derivative mixture in a first solvent,for example, an organic solvent, such as a polar organic solvent. Thepolar organic solvent can be any solvent that can dissolve the crudewater-soluble vitamin E derivative mixture, such as a polar proticsolvent, for example, an alcohol, e.g., methanol, ethanol, propanol orbutanol. In the methods, the amount of first solvent, e.g., polarorganic solvent, used to dissolve the crude water-soluble vitamin Ederivative mixture can be based on the ratio of the volume of the firstsolvent to the volume of the crude water-soluble vitamin E derivativemixture. The ratio of the volume of the first solvent to the volume ofthe crude water-soluble vitamin E derivative mixture can range from0.1:1 to 10:1. In some embodiments, the ratio of the volume of the firstsolvent to the volume of the crude TPGS composition is or is about0.1:1, 0.2:1, 0.25:1, 0.3:1, 0.4:1, 0.45:1, 0.5:1, 0.6:1, 0.7:1, 0.75:1,0.8:1, 0.9:1, 1:1, 1.2:1, 1.25:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1,1.75:1, 1.8:1, 1.9:1, 2:1, 2.5:1, 3:1, 3.5:1, 3.6:1, 4:1, 4.5:1, 5:1,5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, or 10:1 or more.For example, the ratio of the volume of the first solvent to the volumeof the crude water-soluble vitamin E derivative mixture can be 2:1.

The wash can be performed using a second solvent, for example, anorganic solvent, that is not miscible with the first solvent, i.e., thesolvent used to dissolve the crude water-soluble vitamin E derivativemixture. The second solvent can be any solvent that is not miscible withthe first solvent, for example, any solvent that is not miscible with apolar protic solvent such as an alcohol. Suitable organic solvents thatcan be used as a second solvent include non-polar organic solvents, suchas hydrocarbons, e.g., alkanes and cycloalkanes, such as hexane andcyclohexane; halogenated hydrocarbons, e.g., chloroform anddichloromethane; ethers, e.g., diethyl ether; and aromatics, e.g.,benzene and toluene. In the methods, the amount of second solvent, e.g.,a non-polar organic solvent immiscible with the first solvent, used towash the crude water-soluble vitamin E derivative mixture dissolved inthe first solvent can be based on the ratio of the volume of the secondsolvent to the volume of the crude water-soluble vitamin E derivativemixture. The ratio of the volume of the second solvent to the volume ofthe crude water-soluble vitamin E derivative mixture can range from0.1:1 to 10:1. In some embodiments, the ratio of the volume of secondsolvent to the volume of crude water-soluble vitamin E derivativemixture is or is about 0.1:1, 0.2:1, 0.25:1, 0.3:1, 0.4:1, 0.45:1,0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1, 0.9:1, 1:1, 1.2:1, 1.25:1, 1.3:1,1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.75:1, 1.8:1, 1.9:1, 2:1, 2.5:1, 3:1,3.5:1, 3.6:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1,8.5:1, 9:1, 9.5:1, or 10:1 or more. For example, the ratio of the volumeof the second solvent to the volume of the crude water-soluble vitamin Ederivative mixture can be 3:1.

The purification process of the methods, for example, a wash withorganic solvent, can be performed one or more times on the crudewater-soluble vitamin E derivative mixture, for example, two times,three times, four times, or more. The wash can be performed whilestirring. In an exemplary method, the crude water-soluble vitamin Ederivative mixture can be dissolved in a first solvent, for example, aprotic polar organic solvent, e.g., an alcohol, and washed three or moretimes with a second solvent, for example, a non-polar organic solventnot miscible in the first solvent, e.g., a hydrocarbon.

Exemplary of the methods is a method of purifying a crude water-solublevitamin E derivative mixture by performing a purification process, suchas a wash with an organic solvent, e.g., by dissolving the crudewater-soluble vitamin E derivative mixture in methanol and washing withcyclohexane, and repeating the wash with the cyclohexane three or moretimes.

The crude water-soluble vitamin E derivative mixture can be furtherpurified in order to obtain a purified water-soluble vitamin Ederivative mixture, for example, a purified TPGS composition. Thepurified water-soluble vitamin E derivative mixture can be a purifiedTPGS composition that contains less TPGS monomer, i.e., less than 70 wt%, and more TPGS dimer, i.e., more than 12 wt %, than known TPGScompositions. The further purification can be performed to removeimpurities from the crude water-soluble vitamin E derivative mixture.The further purification can be performed in order to isolate thepurified water-soluble vitamin E derivative mixture from the firstsolvent. For example, the crude water-soluble vitamin E derivativemixture can be further purified by treating the crude water-solublevitamin E derivative mixture with an adsorbent, such as activatedcharcoal (i.e., activated carbon). Activated charcoal can be used as adecolorizer and to remove impurities by chemical adsorption. Anyactivated charcoal known to those of skill in the art can be used totreat the crude water-soluble vitamin E derivative mixture. Suchactivated charcoal is available from commercial sources under such tradenames as Calgon-Type CPG®, Type PCB®, Type SGL®, Type CAL®, and TypeOL®.

Further purification of the crude water-soluble vitamin E derivativemixture, for example, treating the crude water-soluble vitamin Ederivative mixture with activated charcoal, can take place for a periodof time of from at or about 0.5 hours to at or about 5 hours, or longerif required. The crude water-soluble vitamin E derivative mixture to betreated can be dissolved in a solvent, for example, the first solventused in the wash described above. Additional solvent can be added, forexample, the same solvent used to dissolve the crude water-solublevitamin E derivative mixture during the wash, e.g., a polar proticorganic solvent. In the methods, the amount of additional solvent, e.g.,polar protic organic solvent, added to the crude water-soluble vitamin Ederivative mixture can be based on the ratio of the total volume of thesolvent, e.g., the first solvent, such as a polar protic organicsolvent, plus the additional solvent, to the volume of the crudewater-soluble vitamin E derivative mixture. The ratio of the totalvolume of the first solvent plus the additional solvent to the volume ofthe crude TPGS composition can range from 0.1:1 to 10:1. In someembodiments, the ratio of the volume of total solvent to the volume ofcrude water-soluble vitamin E derivative mixture is or is about 0.1:1,0.2:1, 0.25:1, 0.3:1, 0.4:1, 0.45:1, 0.5:1, 0.6:1, 0.7:1, 0.75:1, 0.8:1,0.9:1, 1:1, 1.2:1, 1.25:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.75:1,1.8:1, 1.9:1, 2:1, 2.5:1, 3:1, 3.5:1, 3.6:1, 4:1, 4.5:1, 5:1, 5.5:1,6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, or 10:1 or more. Forexample, the ratio of the total volume of the first solvent plusadditional solvent to the volume of the crude water-soluble vitamin Ederivative mixture can be 5:1.

In the methods, further purification, such as treating the reactionmixture with, for example, activated charcoal, can take place for atleast or about at least 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours,4 hours, 5 hours, or longer. The further purification, for example,treating the reaction mixture with activated charcoal, can be done atany temperature of from at or about room temperature, i.e., at or about20° C., to a temperature elevated from room temperature. For example,the temperature of the purification process, e.g., activated charcoaltreatment, can be at or about 20° C., 30° C., 40° C., 50° C., 55° C.,60° C., 70° C., 80° C., 90° C., or 100° C., or any temperature between20° C. and 100° C., such as between or about between 55° C. and 60° C.The treatment temperatures and times can be varied depending on thenature of the crude water-soluble vitamin E derivative mixture, thesolvent, and the impurities present in the crude water-soluble vitamin Ederivative mixture. In an exemplary purification process, such as anactivated charcoal treatment process, the crude water-soluble vitamin Ederivative mixture can be treated, e.g., with activate charcoal, for atleast or about at least 1 hour at a temperature of between or aboutbetween 55° C. and 60° C., before cooling.

In the methods, the crude water-soluble vitamin E derivative mixture canbe filtered and washed after cooling, such as cooling to roomtemperature, i.e., at or about 20° C., after further purification, suchas after treating the crude water-soluble vitamin E derivative mixturewith activated charcoal. The crude water-soluble vitamin E derivativemixture, for example, the crude water-soluble vitamin E derivativemixture dissolved in a solvent, can be filtered and washed, for example,to remove the activated charcoal from the crude water-soluble vitamin Ederivative mixture. For example, the crude water-soluble vitamin Ederivative mixture, for example, the crude water-soluble vitamin Ederivative mixture dissolved in a solvent, can be filtered through afilter aid, such as diatomaceous earth. Suitable filter aids for use inthe methods include, for example, those sold under the trademarksCelite® and Hyflo®. After filtering through a filter aid, such asdiatomaceous earth, the crude TPGS composition can be washed, forexample, with the same solvent used to dissolve the crude water-solublevitamin E derivative mixture, e.g., the first solvent. In an exemplaryembodiment, after further purification, e.g., treatment with activatedcharcoal, and cooling, e.g., to room temperature, i.e., at or about 20°C., the crude water-soluble vitamin E derivative mixture is filteredthrough diatomaceous earth, e.g., Hyflo® filter aid and washed withsolvent, e.g., methanol.

In the methods, the crude water-soluble vitamin E derivative mixture canbe further purified in order to isolate the purified water-solublevitamin E derivative mixture from the solvent, e.g., the first solvent.For example, the crude water-soluble vitamin E derivative mixture can befurther purified by removing the solvent from the water-soluble vitaminE derivative mixture dissolved in solvent, i.e., concentrating the crudewater-soluble vitamin E derivative mixture, in order to obtain apurified water-soluble vitamin E derivative mixture. Any method ofremoving a solvent from a composition known to those of skill in the artcan be used, including, for example, vacuum distillation, rotaryevaporation and filtration. Removing the solvent from the water-solublevitamin E derivative mixture can be done at any temperature, for exampleat room temperature, i.e., 20° C., or at a temperature elevated fromroom temperature. For example, the solvent can be removed at atemperature of at or about 20° C., 30° C., 40° C., 50° C., 55° C., 60°C., 70° C., 80° C., or 90° C., but below or about below 100° C., such asbelow or about below 60° C. In an exemplary embodiment, the solvent canbe removed from the crude water-soluble vitamin E derivative mixture bydistillation, e.g., vacuum distillation, at a temperature elevated fromroom temperature, i.e., at or about 20° C., but below or about below 60°C. After removing the solvent, the purified water-soluble vitamin Ederivative mixture can be dried by any method of drying known to thoseof skill in the art. Suitable methods of drying include drying under aninert gas, for example, nitrogen or argon, or drying under vacuum, orany combination thereof.

In exemplary embodiments of the methods, further purification of thecrude water-soluble vitamin E derivative mixture produced by the methodscan include further purification by treating the crude water-solublevitamin E derivative mixture to remove impurities from the reactionmixture, such as by treating the crude water-soluble vitamin Ederivative mixture with activated charcoal. Further purification of thecrude water-soluble vitamin E derivative mixture produced by the methodscan include further purification by removing the solvent from the crudewater-soluble vitamin E derivative mixture, for example, a crudewater-soluble vitamin E derivative mixture dissolved in a solvent, suchas by removing the solvent by vacuum distillation. The furtherpurification can include treating the crude water-soluble vitamin Ederivative mixture with activated charcoal or removing the solvent fromthe crude water-soluble vitamin E derivative mixture or both. In anexemplary method, the further purification of the crude water-solublevitamin E derivative mixture includes removing the impurities from thecrude water-soluble vitamin E derivative mixture, e.g., treating thecrude water-soluble vitamin E derivative mixture with activatedcharcoal, and removing the solvent from the crude water-soluble vitaminE derivative mixture, e.g., removing the solvent by vacuum distillation,in order to obtain a purified water-soluble vitamin E derivativemixture, for example, a purified TPGS composition. The purified TPGScomposition can contain less TPGS monomer, i.e., less than 70 wt %, andmore TPGS dimer, i.e., more than 12 wt %, than in known TPGScompositions.

The methods yield a purified water-soluble vitamin E derivative mixture,such as a purified TPGS composition, with the desired amount of dimer(greater than 12%) that can be used in any application wherewater-soluble vitamin E derivative mixtures are used, such as in food,beverage, pharmaceutical or nutraceutical products for humanconsumption, and particularly to prepare concentrates that contain thewater-soluble vitamin E derivative composition and a non-polaringredient(s) and other optional ingredients. For example, the methodsproduce a purified water-soluble vitamin E derivative mixture, such as apurified TPGS composition, for example, a TPGS composition that containsless TPGS monomer, i.e., less than 70 wt %, and more TPGS dimer, i.e.,more than 12 wt %, than in known TPGS compositions, that can be used inproducts for human consumption, for example, food and beverage products,particularly aqueous food and beverage products, and any otherapplication in which a water-soluble vitamin E derivative mixture can beadded. Exemplary purified water-soluble vitamin E derivative mixtures(compositions) that can be prepared following the methods are those thatcontain less than 70 wt % monomer and more than 12 wt % dimer, such assuch as compositions containing between or about between 25 wt % and 69wt % monomer and between or about between 13 wt % and 95 wt % dimer,such as compositions containing between or about between 40 wt % and 60wt % monomer and between or about between 25 wt % to 60 wt % dimer. Forexample, the methods can be followed to obtain water-soluble vitamin Ederivative mixtures (compositions) that contain between or about between25 wt % and 69 wt % monomer, for example, at or about 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68 or 69 wt % monomer and between or about between 13 wt %and 95 wt % dimer, for example, at or about 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94 or 95 wt % dimer.

These methods are described with reference to TPGS and can be adapted toproduce any higher dimer-containing water-soluble vitamin E derivativecomposition. Other methods to produce compositions with the desireddimer or dimer and monomer concentrations can be employed, includingpurifying dimer from standard preparations and adding the dimer back toa standard preparation to increase its concentration. The resultingcompositions are employed in the concentrates and dilution compositionsdescribed herein.

D. Products Containing High Dimer-Containing Water-Soluble Vitamin EDerivative Mixtures

Provided herein are products containing the high dimer-containingwater-soluble vitamin E mixtures. These include, for example, productsfor human consumption, such as food and beverage products, in particularaqueous food and beverage products, and soft gel capsules containingemulsions for direct consumption, as well as methods for making theproducts. In particular, provided are pre-emulsion concentrates, pre-gelconcentrates, liquid nanoemulsion concentrates, soft gel compositions(capsules), and liquid dilution (beverage) compositions containing theconcentrates, and other beverage compositions that contain thewater-soluble vitamin E derivative mixtures (compositions) as describedherein. Also provided are compositions for direct consumption in thatthe water-soluble vitamin E derivative mixture and other ingredients arepresent in amounts for direct ingestion. The water-soluble vitamin Ederivative mixture is typically present in an amount of less than 10%,generally in an amount of about 1%-5%.

The compositions provided herein that contain the water-soluble vitaminE derivative mixtures described herein can contain non-polaringredients. Non-polar ingredients are poorly water-soluble (e.g., havelow water solubility or are water-insoluble). Thus, it generally can bedifficult to formulate non-polar ingredients into products for humanconsumption, particularly aqueous products, for example, food andbeverage compositions. Poor water solubility of non-polar ingredientsalso can contribute to their poor bioavailability. Improved methods andcompositions for formulating food and beverage products containingnon-polar ingredients are provided herein. The products containing thewater-soluble vitamin E derivative mixtures described herein can containhigher concentrations of non-polar ingredients as compared to availablefood and beverage products. The products containing the water-solublevitamin E derivative mixtures (compositions) can solubilize higheramounts of non-polar ingredients than in products containing suchwater-soluble vitamin E with lower concentrations (i.e., less than 13%,29%, 35%, 52%) of dimers. These resulting products retain desirableorganoleptic properties, such as clarity (i.e., low turbidity). Theproducts provided herein can contain high amounts of non-polaringredient, such as non-polar ingredients that are or contain non-polarcompounds, for example, between or between about 1 wt % and 75 wt %non-polar ingredient, such as between or between about 1% and 5%, 1% and10%, 1% and 15%, 1% and 20%, 1% and 25%, 1% and 30%, 1% and 35%, 1% and40%, 1% and 45%, 1% and 50%, 1% and 55%, 1% and 60%, 1% and 65%, 1% and70%, 1% and 75%, 5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and30%, 5% and 35%, 5% and 40%, 5% and 45%, 5% and 50%, 5% and 55%, 5% and60%, 5% and 65%, 5% and 70%, 5% and 75%, 10% and 15%, 10% and 20%, 10%and 25%, 10% and 30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% and50%, 10% and 55%, 10% and 60%, 10% and 65%, 10% and 70%, 10% and 75%,15% and 20%, 15% and 25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and45%, 15% and 50%, 15% and 55%, 15% and 60%, 15% and 65%, 15% and 70%,20% and 25%, 20% and 30%, 20% and 35%, 20% and 40%, 20% and 45%, 20% and50%, 20% and 55%, 20% and 60%, 20% and 65%, 20% and 70%, 20% and 75%,25% and 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and55%, 25% and 60%, 25% and 65%, 25% and 70%, 25% and 75%, 30% and 35%,30% and 40%, 30% and 45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% and65%, 30% and 70%, 30% and 75%, 35% and 40%, 35% and 45%, 35% and 50%,35% and 55%, 35% and 60%, 35% and 65%, 35% and 70%, 35% and 75%, 40% and45%, 40% and 50%, 40% and 55%, 40% and 60%, 40% and 65%, 40% and 70%,40% and 75%, 45% and 50%, 45% and 55%, 45% and 60%, 45% and 65%, 45% and70%, 45% and 75%, 50% and 55%, 50% and 60%, 50% and 65%, 50% and 69%,55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 60% and 65%, 60% and70%, 60% and 75%, 65% and 70%, 65% and 75% and 70% and 75%, by weight,of the food or beverage product. The products that contain thewater-soluble vitamin E derivative mixtures and high amounts ofnon-polar ingredient retain desirable organoleptic properties, such asremaining free from turbidity. For example, the products provided hereincan contain up to twice the amount of non-polar ingredient as availableproducts that contain known TPGS compositions and retain the same levelof turbidity. Products that contain known TPGS compositions, such asproducts that contain TPGS compositions made up of mostly monomer (e.g.,70% or greater) and a small amount of dimer (e.g., 12% or less), and ahigh amount of non-polar ingredient, e.g., up to 75 wt % non-polaringredient, exhibit higher turbidity levels, for example, a two-foldhigher turbidity level, as compared to the products provided herein thatcontain the TPGS compositions provided herein and the same amount ofnon-polar ingredient, e.g., up to 75 wt % non-polar ingredient.

The water-soluble vitamin E derivative mixtures (compositions) providedherein can be formulated with non-polar ingredients that are or containnon-polar compounds to form a pre-emulsion concentrate. Thewater-soluble vitamin E derivate compositions described herein can beformulated with non-polar ingredients that are or contain non-polarcompounds and additional ingredients, such as a polar solvent, to formliquid nanoemulsion concentrates. The liquid nanoemulsion concentratesthat contain the water-soluble vitamin E derivative mixtures(compositions) described herein and the non-polar ingredients can bediluted to form liquid dilution compositions that contain thewater-soluble vitamin E derivative mixtures (compositions) describedherein and non-polar ingredients that are or contain non-polarcompounds. The liquid dilution compositions that are produced are clearor remain clear.

The water-soluble vitamin E derivative mixtures (compositions) providedherein can be formulated with non-polar ingredients that are or containnon-polar compounds or other ingredients to form a composition fordirect consumption, such as a beverage composition. These compositionscan be formulated in a variety of volumes and sizes, including, but notlimited to, a single-serving shot and a multi-serving composition. Thebeverage compositions that are produced are clear and typically remainclear.

Concentrates and compositions for direct consumption that contain thewater-soluble vitamin E derivative mixtures (compositions) describedherein and a non-polar component are provided. The concentrates containfrom 99% or more of the water-soluble vitamin E derivative compositionwith the remainder as a non-polar ingredient, to as little as 1%,typically 5%, of the water-soluble vitamin E derivative composition. Thecompositions for direct consumption contain from 50% or more of thewater-soluble vitamin E derivative composition to as little as 0.1%,typically 1.5%, of the water-soluble vitamin E derivative composition.Further description and examples are provided below. The concentratesand compositions for direct consumption can contain additional optionalingredients, including polar solvents, such as water and/or alcohol.

Depending upon the amount of water-soluble derivative of vitamin E, theconcentrates are waxy or creamy (semi-solids) or liquids, includingemulsions, depending upon the particular components and amounts thereof.The concentrates are added to foods, particularly beverages, includingaqueous beverages, that contain desired amounts of the non-polaringredients, by adding an appropriate amount of an appropriateconcentrate to the beverage. For example, the concentrate can bedissolved and diluted to form a liquid dilution composition.Alternatively, the water-soluble vitamin E derivative mixtures(compositions) can be formulated directly into a beverage composition.For example, the water-soluble vitamin E derivative mixtures(compositions) can be added to the beverage composition withoutformulating a concentrate. The resulting food/beverage compositionsretain desirable organoleptic properties, such as improved clarity(e.g., small particle size, low turbidity), stability (e.g., lack ofseparation), taste and smell. Food and beverage compositions that retaindesirable organoleptic properties are needed. The emulsions providedherein address those needs among others.

Among the compositions for direct consumption and concentrates describedherein are concentrates that are semi-solid waxes and emulsions, wherethe concentrates and compositions for direct consumption also contain apolar solvent, such as water or alcohol. The emulsions provided hereincontain the water-soluble vitamin E derivative mixtures describedherein.

It is shown herein that the water-soluble vitamin E derivative mixtures(high dimer-containing) described herein permit higher amounts ofnon-polar ingredients to be dispersed in an aqueous liquid thancompositions containing water-soluble vitamin E derivative mixtures withlow dimer amounts. For example, oil-in-water emulsions are provided thatcontain water-soluble vitamin E derivative mixtures and non-polaringredients dispersed in an aqueous liquid that have desirableproperties, including improved clarity, stability, smell and taste. Theprovided emulsions (and methods for making the emulsions) can be used toformulate any non-polar ingredient in an aqueous composition, includingthe non-polar ingredients (e.g., non-polar ingredients that are orcontain non-polar compounds) described herein and other known non-polarcompounds and ingredients. Typically, the provided compositionscontaining the water-soluble vitamin E derivatives are emulsions.Typically, the provided emulsion compositions are oil-in-waternanoemulsions that contain the non-polar ingredients dispersed inaqueous liquid.

The provided emulsion compositions can be further stabilized byinclusion of one or more co-surfactants and/or emulsion stabilizers inaddition to the water-soluble vitamin E derivatives described herein.Surfactants form an interfacial film in the emulsion between the oil andwater phase, providing stability. Typically, the nanoemulsions of theprovided compositions contain micelles in which one or more surfactantssurround the non-polar compound. The micelles are dispersed in the waterphase.

The provided emulsion compositions include liquid nanoemulsionconcentrates containing the water-soluble vitamin E derivativesdescribed herein and non-polar ingredients, which can be diluted toprovide non-polar ingredients in aqueous compositions, such as beverageproducts. The liquid nanoemulsion concentrates can be diluted into amedium, for example, an aqueous medium, to form a liquid dilutioncomposition (e.g., an aqueous liquid dilution composition) containingthe non-polar ingredients. Also exemplary of the provided compositionsare the liquid dilution compositions (e.g., aqueous liquid dilutioncompositions) made by diluting the liquid nanoemulsion concentrates inthe medium, that remain clear.

The emulsion compositions and food and beverage products provided hereincan contain any non-polar ingredient or compound. The non-polaringredients typically are non-polar compounds, for example,pharmaceuticals, nutraceuticals, vitamins and minerals. The non-polaringredients include, but are not limited to, polyunsaturated fatty acid(PUFA)-containing compounds, such as omega-3-containing ingredients, forexample, compounds containing ALA, DHA and/or EPA, e.g., oils derivedfrom fish and microalgae, krill and/or flaxseed extract, andomega-6-containing non-polar compounds, for example, gamma-linolenicacid (GLA)-containing compounds, e.g., borage oil; saw palmettooil-containing compounds; conjugated fatty acid containing-ingredients,for example, conjugated linoleic acid (CLA)-containing compounds;coenzyme Q-containing ingredients, for example, coenzyme Q10 (coQ10),e.g., oxidized coQ10 (ubidecarenone)-containing compounds; and compoundscontaining phytosterols (plant sterols). Additional exemplary non-polaringredients and other compounds are described herein. Any non-polarcompound or ingredient can be used in the provided emulsion compositionsand food and beverage products provided herein.

1. Exemplary Ingredients and Exemplary Concentration Ranges

The following sections describe ingredients used in the providedpre-emulsion concentrates and liquid nanoemulsion concentrates or otherforms of concentrates and beverage compositions. As noted, the form ofthe resulting composition containing the high dimer-containingwater-soluble vitamin E derivative mixture depends upon theconcentration ranges and types of ingredients. Concentrates typicallyare intended for dilution prior to consumption, and, thus, containnon-polar ingredients in higher than single dosage concentrations. Wherehigh concentration of the water-soluble vitamin E derivative mixturesare employed (typically greater than 25% or about 25%), particularlywithout any liquid components, the compositions are waxy. Where lowerconcentrations are used, the compositions can be more liquid; wherepolar solvents and or other polar ingredients are included, theconcentrates are emulsions. All can be used as vehicles for solubilizingdesired non-polar ingredients in food and beverages.

Each of the provided concentrates, e.g., pre-emulsion concentrates andliquid nanoemulsion concentrates, and semi-solids, and beveragecompositions, e.g., liquid dilution compositions and single-servingshots, contain at least one surfactant that is a water-soluble vitamin Ederivative mixture described herein, for example, the TPGS, TPGSanalogs, TPGS homologs and TPGS derivative mixtures described herein.The surfactant typically has an HLB value of between 12 or about 12 and20 or about 20, for example, 12, 13, 14, 15, 16, 17, 18, 19 or 20, orabout 12, about 13, about 14, about 15, about 16, about 17, about 18,about 19, or about 20, typically between at or about 12 and at or about14. For example, TPGS, such as the TPGS described herein, has an HLBvalue of about 12 to 14, generally about 13.

For compositions that are to be diluted, the water-soluble vitamin Ederivative mixture, e.g., TPGS, is typically present in an amount as apercentage (%), by weight, of the concentrate (wt %), e.g., from at orabout 20% to at or about 90%, such as 20% to 25%, 20% to 30%, 20% to35%, 20% to 40%, 20% to 45%, 20% to 50%, 20% to 55%, 20% to 60%, 20% to65%, 20% to 70%, 20% to 75%, 20% to 80%, 20% to 85%, 20% to 90%, 25% to30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 25% to 55%, 25% to60%, 25% to 65%, 25% to 70%, 25% to 75%, 25% to 80%, 25% to 85%, 25% to90%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 30% to 55%, 30% to60%, 30% to 65%, 30% to 70%, 30% to 75%, 30% to 80%, 30% to 85%, 30% to90%, 35% to 40%, 35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, 35% to65%, 35% to 70%, 35% to 75%, 35% to 80%, 35% to 85%, 35% to 90%, 40% to45%, 40% to 50%, 40% to 55%, 40% to 60%, 40% to 65%, 40% to 70%, 40% to75%, 40% to 80%, 40% to 85%, 40% to 90%, 45% to 50%, 45% to 55%, 45% to60%, 45% to 65%, 45% to 70%, 45% to 75%, 45% to 80%, 45% to 85%, 45% to90%, 50% to 55%, 50% to 60%, 50% to 65%, 50% to 70%, 50% to 75%, 50% to80%, 50% to 85%, 50% to 90%, 55% to 60%, 55% to 65%, 55% to 70%, 55% to75%, 55% to 80%, 55% to 85%, 55% to 90%, 60% to 65%, 60% to 70%, 60% to75%, 60% to 80%, 60% to 85%, 60% to 90%, 65% to 70%, 65% to 75%, 65% to80%, 65% to 85%, 65% to 90%, 70% to 75%, 70% to 80%, 75% to 85%, 75% to90%, 80% to 85%, 80% to 90%, or 85% to 90%, by weight, of theconcentrate. Exemplary concentrations of the water-soluble vitamin Ederivative mixture, e.g., TPGS, in the pre-emulsion concentrate are ator about 20%, 25%, 30%, 35%, 40%, 45%, 49.5%, 50%, 55%, 60%, 65%, 68%,69.5%, 70%, 75%, 79.5%, 80%, 85%, 89.5% and 90% (wt %) of theconcentrate. The concentrates can contain lower amounts of thewater-soluble vitamin E derivative mixture, and the compositions fordirect consumption contain lower amounts, such as 1%-15%, generally1%-5%.

Each of the provided compositions, e.g., pre-emulsion concentrates andliquid nanoemulsion concentrates, further contains a non-polaringredient including, but not limited to, the exemplary non-polaringredients described herein below. Typically, the non-polar ingredientis or contains one or more non-polar compounds, for example, anoil-based non-polar ingredient, such as a polyunsaturated fatty acid(PUFA), a coenzyme Q or a phytochemical. The concentrates providedherein can contain one non-polar ingredient or more than one non-polaringredient, such as two, three, four, five or more non-polaringredients. The concentrates provided herein can contain higher amounts(i.e., concentrations) of non-polar ingredients than can availableconcentrates, such as up to at or about 75 wt % non-polar ingredients.

For formulating the concentrates, the total amount of non-polaringredient(s) that is or contains one or more non-polar compounds istypically present in a total amount as a percentage (%), by weight, ofthe concentrate (wt %), e.g., from at or about 1% to at or about 75 wt%, such as between or between about 1% and 5%, 1% and 10%, 1% and 15%,1% and 20%, 1% and 25%, 1% and 30%, 1% and 35%, 1% and 40%, 1% and 45%,1% and 50%, 1% and 55%, 1% and 60%, 1% and 65%, 1% and 70%, 1% and 75%,5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and 30%, 5% and 35%,5% and 40%, 5% and 45%, 5% and 50%, 5% and 55%, 5% and 60%, 5% and 65%,5% and 70%, 5% and 75%, 10% and 15%, 10% and 20%, 10% and 25%, 10% and30%, 10% and 35%, 10% and 40%, 10% and 45%, 10% and 50%, 10% and 55%,10% and 60%, 10% and 65%, 10% and 70%, 10% and 75%, 15% and 20%, 15% and25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% and 50%,15% and 55%, 15% and 60%, 15% and 65%, 15% and 70%, 20% and 25%, 20% and30%, 20% and 35%, 20% and 40%, 20% and 45%, 20% and 50%, 20% and 55%,20% and 60%, 20% and 65%, 20% and 70%, 20% and 75%, 25% and 30%, 25% and35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and 55%, 25% and 60%,25% and 65%, 25% and 70%, 25% and 75%, 30% and 35%, 30% and 40%, 30% and45%, 30% and 50%, 30% and 55%, 30% and 60%, 30% and 65%, 30% and 70%,30% and 75%, 35% and 40%, 35% and 45%, 35% and 50%, 35% and 55%, 35% and60%, 35% and 65%, 35% and 70%, 35% and 75%, 40% and 45%, 40% and 50%,40% and 55%, 40% and 60%, 40% and 65%, 40% and 70%, 40% and 75%, 45% and50%, 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%, 45% and 75%,50% and 55%, 50% and 60%, 50% and 65%, 50% and 69%, 55% and 60%, 55% and65%, 55% and 70%, 55% and 75%, 60% and 65%, 60% and 70%, 60% and 75%,65% and 70%, 65% and 75%, or 70% to 75% non-polar ingredient, by weight,of the concentrate. Exemplary concentrations of the total amount ofnon-polar ingredient(s) in the concentrate is at or about 5%, 10%,12.5%, 15%, 15.5%, 16.7%, 20%, 22%, 25%, 30%, 31.5%, 35%, 40%, 45.5% and50% (wt %) of the concentrate.

The concentrates, e.g., the pre-emulsion concentrates and liquidnanoemulsion concentrates, can further contain additional ingredients,for example, preservatives and/or non-polar solvents. In some examples,the preservative is a natural preservative, such as benzyl alcohol. Insome examples, the non-polar solvent is an oil, other than the non-polaringredient, for example, vitamin E oil, flaxseed oil or rice bran oil.

The liquid nanoemulsion concentrates additionally contain at least onepolar solvent. Exemplary polar solvents include water, propylene glycoland glycerin (glycerol). One or more, typically more than one,additional ingredients can be added to the liquid nanoemulsionconcentrate. Exemplary of other additional ingredients that can be addedto the liquid concentrates include emulsion stabilizers, for example, ablend of gums; a pH adjuster, for example, citric acid or phosphoricacid; one or more flavoring agents, for example, D-limonene or lemonoil; a co-surfactant, for example, a phospholipid, e.g.,phosphatidylcholine, or a sucrose fatty acid ester surfactant.

The appropriate concentration ranges for the additional ingredients aredescribed in individual sections below. Typically, the concentration ofthe additional ingredients depends, in part, on the concentrations ofthe non-polar ingredient and the water-soluble vitamin E derivativesurfactant. Typically, the concentrations of these ingredients(surfactant and non-polar ingredient) are the focus of the formulatingmethods. For example, when it is determined that modifications toingredient concentrations in the initial concentrate should be made, ittypically is the concentrations of one or more of these ingredients thatare adjusted.

In one example, it can be desirable to add one or more of the additionalingredients after evaluation of the initial concentrate, for example, inorder to improve the concentrate with respect to one or more desiredproperties.

a. Water-Soluble Vitamin E Derivatives

The compositions for direct consumption, the pre-emulsion concentratesand liquid nanoemulsion concentrates provided herein, contain the highdimer-containing water-soluble vitamin E derivative mixtures describedherein, for example, the TPGS compounds noted above, including TPGS,TPGS homologs, TPGS analogs and TPGS derivatives and other vitamin Ederivatives. The water-soluble vitamin E derivative mixtures can act assurfactants. The water-soluble vitamin E derivative mixtures can be anyof the high dimer-containing water-soluble vitamin E derivative mixturesdescribed herein, for example, tocopherol-derived compositions andtocotrienol-derived compositions, including, but not limited to,polyalkylene glycol derivatives of tocopherol, e.g., polyethylene glycol(PEG) derivatives of tocopherol, such as vitamin E TPGS (D-α-tocopherylpolyethylene glycol succinate), and polyalkylene glycol derivatives oftocotrienol, e.g., polyethylene glycol (PEG) derivatives of tocotrienol.The high dimer-containing water-soluble vitamin E derivative mixtures(compositions), e.g., compositions of TPGS, TPGS analogs, TPGS homologsor TPGS derivatives, contain less water-soluble vitamin E derivativemonomer, i.e., less than 70 wt %, and more water-soluble vitamin Ederivative dimer, i.e., more than 12 wt %, than in known water-solublevitamin E derivative mixtures (compositions).

In the concentrates provided herein, e.g., the pre-emulsionconcentrates, pre-gel concentrates and liquid nanoemulsion concentrates,the water-soluble vitamin E derivatives can act as surfactants byaggregating in aqueous liquids, such as water, to form micelles, whichcontain the non-polar ingredient(s). The hydrophilic portion(s) of thesurfactant molecules are oriented toward the outside of the micelle, incontact with the aqueous medium, while the hydrophobic portion(s) of thesurfactant molecules are oriented toward the center of the micelle, incontact with the non-polar ingredient(s), which is contained in thecenter of the micelle. Properties of the provided food and beverageproducts, for example, the particle size of the concentrates anddesirable properties related to the particle size, are influenced by thechoice of surfactant(s) and the relative amount (concentration) ofsurfactant. For example, the HLB of the surfactant(s) can affectparticle size, clarity, taste, smell, crystal formation and otherproperties of the provided food and beverage products. Similarly, theconcentration of the surfactant compared with the concentration(s) ofother ingredients, particularly compared with the concentration of thepolar solvent(s) and the concentration of the non-polar ingredient(s),can affect various desirable properties, for example, the ability todisperse or dissolve in aqueous media, e.g., to form a clear aqueousliquid dilution composition or pleasant taste and/or smell. Thewater-soluble vitamin E derivative mixtures (compositions) describedherein can be used to increase the amount of non-polar ingredient thatcan be added to a concentrate, such as the concentrates provided herein,without sacrificing the various desirable properties of the food andbeverage products containing the concentrate, such as particle size,clarity, taste, smell, crystal formation and other desirable propertiesof food and beverage products.

The water-soluble vitamin E derivative mixtures described herein andothers known to those of skill in the art and used in the concentratesprovided herein, e.g., the pre-emulsion concentrates and liquidnanoemulsion concentrates, typically have an HLB value between or aboutbetween 12 and 20, for example, at least 12, 13, 14, 15, 16, 17, 18, 19,up to 20, about 12, about 13, about 14, about 15, about 16, about 17,about 18, about 19 or about 20. Typically, the water-soluble vitamin Ederivative is a natural surfactant, for example, a surfactant that isGRAS (generally recognized as safe) certified by the FDA and/or Koshercertified, for example, TPGS, such as the TPGS derivative mixturesdescribed herein. In one example, the water-soluble vitamin E derivativemixture used in the provided concentrates is a polyalkylene glycolderivative of vitamin E, for example, a polyethylene glycol derivativeof vitamin E, e.g., TPGS. TPGS has an HLB value of or about 13.

At room temperature, TPGS typically is a waxy low-melting solid. TPGScan be heated prior to use, for example, to at least the meltingtemperature, such as between or about between 37° C. and 41° C. or about41° C. and the desired amount is poured out. Alternatively, TPGS can beadded as a waxy solid to a vessel and heated with the heating apparatus.

b. Non-Polar Ingredients

All of the compositions described and provided herein include awater-soluble vitamin E derivative, such as a PEG derivative of vitaminE, such as a TPGS, that is a high dimer-containing mixture (as describedherein) of the water-soluble vitamin E derivative. The compositions allinclude a non-polar ingredient or mixture thereof. The non-polaringredient is or contains a non-polar compound, such as a non-polarbioactive compound, for example, a nutritional supplement or a drug. Thenon-polar ingredients include, but are not limited to, drugs, hormones,vitamins, nutrients and other lipophilic compounds. Exemplary non-polaringredients are listed herein below. The provided methods andcompositions can be used to dilute (e.g., dissolve/disperse) anynon-polar ingredient in aqueous medium, such as water.

The non-polar ingredient is not a water-soluble vitamin E derivative.Exemplary of non-polar ingredients that can be used in the providedpre-emulsion concentrates and liquid nanoemulsion concentrates are:

non-polar ingredients containing essential fatty acids, such aspolyunsaturated fatty acids (PUFAs), for example, gamma-linolenic acid(GLA), e.g., borage oil and evening primrose (Oenothera biennis) oil,blackcurrant seed oil, hemp seed oil and spirulina extract; compoundscontaining omega-3 fatty acids, such as natural and synthetic omega-3fatty acids, for example, compounds containing omega-3 polyunsaturatedlong-chain fatty acids, including eicosapentaenoic acid (EPA) (20:5ω3);docosahexaenoic acid (DHA) (22:6ω3); eicosatetraenoic acid (20:4 ω3);docosapentaenoic acid (DPA, clupanodonic acid) (22:5ω3); 16:3 ω3; 24:5ω3 and/or nisinic acid (24:6ω3), e.g., fish oil, algae oil, krill oil,canola oil, flaxseed oil, soybean oil and walnut oil; compoundscontaining short-chain omega-3 fatty acids, for example, alpha-linolenicacid (α-linolenic acid; ALA; 18:3ω3) and stearidonic acid (18:4ω3),esters of an omega-3 fatty acid and glycerol, for example,monoglycerides, diglycerides and triglycerides, esters of omega-3 fattyacid and a primary alcohol, for example, fatty acid methyl esters andfatty acid esters, precursors of omega-3 fatty acid oils, for example,EPA precursor, DHA precursor, derivatives such as polyglycolizedderivatives or polyoxyethylene derivatives, oils containing the omega-3fatty acids, for example, fish oil (marine oil), e.g., highly purifiedfish oil concentrates, perilla oil, krill oil, and algae oil, e.g.,microalgae oil; compounds containing omega-6 fatty acids, such ascompounds containing linoleic acid (18:2ω6) (a short-chain fatty acid);gamma-linolenic acid (GLA; 18:3ω6); dihomo gamma linolenic acid (DGLA;20:3ω6); eicosadienoic acid (20:2ω6); arachidonic acid (AA; 20:4ω6);docosadienoic acid (22:2ω6); adrenic acid (22:4ω6); and/ordocosapentaenoic acid (22:5ω6), for example, borage oil, corn oil,cottonseed oil, grapeseed oil, peanut oil, primrose oil, e.g., eveningprimrose (Oenothera biennis) oil, blackcurrant seed oil, hemp seed oil,spirulina extract, safflower oil, sesame oil, coconut oil and soybeanoil;

other fatty acids, such as triglycerides, including medium chaintriglycerides, polar lipids, for example, ether lipids, phosphoric acid,choline, fatty acids, glycerol, glycolipids, triglycerides, andphospholipids (e.g., phosphatidylcholine (lecithin),phosphatidylethanolamine, and phosphatidylinositol); saw palmettoextract; ethyl linoleate; herb oils, for example, garlic oils andscordinin; short-chain saturated fatty acids (4:0-10:0), lauric acid(12:0), myristic acid (14:0), pentadecanoic acid (15:0), palmitic acid(16:0), palmitoleic acid (16:1 ω7), heptadecanoic acid (17:0), stearicacid (18:0), oleic acid (18:1 ω9), and arachidic acid (20:0);

micronutrients, such as vitamins, minerals, co-factors, for example,coenzyme Q10 (coQ10, also called ubiquinone), ubiquinol, turmericextract (curcuminoids), saw palmetto lipid extract (saw palmetto oil),echinacea extract, hawthorn berry extract, ginseng extract, lipoic acid(thioctic acid), ascorbyl palmitate, kava extract, St. John's Wort(hypericum, Klamath weed, goat weed), extract of quercitin,dihydroepiandrosterone, and indol-3-carbinol;

carotenoids, including hydrocarbons and oxygenated, alcoholicderivatives of hydrocarbons, for example, beta carotene, mixedcarotenoid complex, lutein, lycopene, zeaxanthin, cryptoxanthin, forexample, beta-cryptoxanthin, beta carotene, astaxanthin, bixin,canthaxanthin, capsanthin, capsorubin, apo-carotenal,beta-12′-apo-carotenal, “Carotene” (mixture of alpha- andbeta-carotene), gamma carotene, ciolerythrin, and esters of hydroxyl- orcarboxyl-containing members thereof;

fat-soluble vitamins, for example, vitamins A, D, E and K, andcorresponding pro-vitamins and vitamin derivatives, such as esters, withan action resembling that of vitamin A, D, E or K, for example; retinol(vitamin A) and pharmaceutically acceptable derivatives thereof, such aspalmitate ester of retinol and other esters of retinol, calciferol(vitamin D) and its pharmaceutically acceptable derivatives thereof andprecursors of vitamin D, d-alpha tocopherol (vitamin E) and derivativesthereof, including pharmaceutical derivatives thereof, for example,tocotrienols, d-alpha tocopherol acetate and other esters of d-alphatocopherol, and ascorbyl palmitate, a fat-soluble version of vitamin C;

phytochemicals, including phytoestrogens, for example, genistein anddaidzein, such as isoflavones, e.g., soy isoflavones, flavonoids,phytoalexins, for example, resveratrol (3,5,4′-trihydroxystilbene), redclover extract, and phytosterols;

lipid-soluble drugs, including natural and synthetic forms ofimmunosuppressive drugs, such as cyclosporin, protease inhibitors suchas ritonavir, macrolide antibiotics and oil soluble anesthetics such aspropofol, natural and synthetic forms of steroidal hormones, forexample, estrogens, estradiols, progesterone, testosterone, cortisone,phytoestrogens, dehydroepiandrosterone (DHEA), growth hormones and otherhormones; and oil-soluble acids and alcohols, for example, tartaricacid, lactylic acid, butylated hydroxyanisole, butylated hydroxytoluene,lignin, sterols, polyphenolic compounds, oryzanol, cholesterol,phytosterols, flavonoids, such as quercetin and resveratrol, and diallyldisulfides.

i. Polyunsaturated Fatty Acid (PUFA)-Containing Ingredients

Exemplary of the non-polar ingredients contained in the concentrates,e.g., pre-emulsion concentrates and liquid nanoemulsion concentrates,are ingredients containing fatty acids, for example, non-polaringredients containing the non-polar compounds polyunsaturated fattyacids (PUFAs). Fatty acids are straight-chain hydrocarbon molecules witha carboxyl (COOH) group at one end of the chain. PUFAs are fatty acidsthat contain more than one carbon-carbon double bonds in the carbonchain of the fatty acid. PUFAs, particularly essential fatty acids, areuseful as dietary supplements.

Different nomenclature is used to describe fatty acid molecules. Lipidnomenclature, for example, 18:3 ω-3, indicates the carbon chain length,number of double bonds and the position along the carbon chain of thefirst carbon-carbon double bond in a fatty acid. Using thisnomenclature, each carbon along the chain is labeled according to itsposition relative to one end of the chain. For example, the first carbonaway from the carboxylate end is named α, the second is named β, and soforth. The last carbon in the molecule (furthest from the carboxy group)always is labeled ω (or omega, or n). The number of carbons and thenumber of double bonds are listed first in the lipid name of a fattyacid, separated by a colon. For example, the name “18:3” indicates thatthe molecule has eighteen (18) carbons and three (3) double bonds.Following these numbers, the position at which the first double bondappears, relative to the last (ω) carbon, is listed. For example, thenomenclature, 18:3 ω-3 (or 18:3 omega-3; or 18:3 n-3), describes a fattyacid with eighteen (18) carbons and three (3) double bonds, the first ofwhich occurs at the third carbon away from the omega carbon.

Alternatively, chemical nomenclature can be used. The chemical name of afatty acid describes the position of each double bond. In the chemicalnaming, the carbons are numbered, beginning with 1, starting with thecarbon that is part of the carboxy (COOH) group. Thus, with thisnumbering system, the α carbon is labeled “2.” The chemical name of thefatty acid lists the first carbon (from the COOH end) to participate ineach double bond.

Certain PUFAs are called essential fatty acids because they are requiredfor biological processes and mammals, including humans, cannotsynthesize them using any known chemical pathway, and therefore mustobtain them from diet or by supplementation (U.S. Pat. No. 6,870,077;Covington (2004) American Family Physician 70(1):133-140). The essentialPUFAs are the omega-3 (ω3; n-3) fatty acids and the omega-6 (ω-6; n-6)fatty acids. Omega-3 and omega-6 fatty acids are methylene interruptedpolyenes which have two or more cis double bonds separated by a singlemethylene group. Exemplary of omega-3 fatty acids are alpha-linolenicacid (α-linolenic acid; ALA; 18:3ω3) (a short-chain fatty acid);stearidonic acid (18:4ω3) (a short-chain fatty acid); eicosapentaenoicacid (EPA; 20:5ω3); docosahexaenoic acid (DHA; 22:6ω3); eicosatetraenoicacid (20:4 ω3); docosapentaenoic acid (DPA; clupanodonic acid; 22:5ω3);16:3 ω3; 24:5 ω3 and nisinic acid (24:6ω3). Longer chain omega-3 fattyacids can be synthesized from ALA (the short-chain omega-3 fatty acid).Exemplary of omega-6 fatty acids are linoleic acid (18:2ω6) (ashort-chain fatty acid); gamma-linolenic acid (GLA; 18:3ω6); dihomogamma linolenic acid (DGLA; 20:3ω6); eicosadienoic acid (20:2ω6);arachidonic acid (AA; 20:4ω6); docosadienoic acid (22:2ω6); adrenic acid(22:4ω6); and docosapentaenoic acid (22:5ω6).

While the longer chain omega-3 and omega-6 essential fatty acids can besynthesized from ALA (the short-chain omega-3 fatty acid) and linolenicacid (LA), respectively, evidence suggests that conversion of theseshort chain fatty acids in humans is slow. Thus, a major source of longchain essential PUFAs is dietary (see, e.g., Ross et al. (2007) Lipidsin Health and Disease 6:21 and Lands (1992) FASEB J. 6(8):2530). Dietarysupplements containing PUFAs, particularly essential PUFAs, aredesirable for protection against cardiovascular disease, inflammationand mental illnesses (see, e.g., Ross et al. (2007) Lipids in Health andDisease 6:21; Lands (1992) FASEB J. 6(8):2530; and U.S. Pat. No.6,870,077). Evidence suggests that essential fatty acids, particularlyEPA and DHA, in the form of food and nutritional supplements, play arole in preventing a number of disease states, including cardiovasculardiseases, inflammation, mental health and behavioral diseases anddisorders (see, e.g., Ross et al. (2007) Lipids in Health and Disease6:21; Lands (1992) FASEB J. 6(8):2530; U.S. Pat. No. 6,870,077; andCovington (2004) American Family Physician 70(1):133-140).

Omega-9 fatty acids are non-essential PUFAs. Exemplary of omega-9 fattyacids are oleic acid (which is monounsaturated) (18:1 ω9); eicosenoicacid (20:1 ω9); mead acid (20:3 ω9); erucic acid (22:1 ω9); and nervonicacid (24:1 ω9).

Conjugated fatty acids are PUFAs with two or more conjugated doublebonds. Conjugated fatty acids can be used as nutritional supplements.Exemplary of conjugated fatty acids are conjugated linoleic acid (CLA),for example, 18:2 ω7, 18:2 ω6; conjugated linolenic acid, for example,18:3ω6, 18:3ω5; and other conjugated fatty acids, for example, 18:3 ω3,18:4 ω3, and 20:5 ω6.

(a) Omega-3 Fatty Acid Compounds

Exemplary of the PUFA-containing non-polar ingredients that can be usedin the provided concentrates, e.g., pre-emulsion concentrates and liquidnanoemulsion concentrates, are non-polar ingredients that contain one ormore of the non-polar compound omega-3 (ω3; n-3) fatty acids, forexample, ingredients containing DHA and/or EPA fatty acids, for example,marine oils, e.g., fish oil, krill oil and algae oil; and compoundscontaining ALA fatty acids, for example, flax seed oil.

Typically, oils and aqueous compositions containing long-chainpolyunsaturated fatty acids (PUFA) are susceptible to oxidation, makingthem unstable and giving them an unpleasant taste. The ingredients andrelative concentrations thereof, as well as the methods for making theconcentrates, contribute to desirable properties of DHA/EPA-containingconcentrates. For example, the ingredients and methods used to make theconcentrates provided herein minimize the “fishy” odor and/or taste ofDHA/EPA compositions and increase their stability over time. Forexample, the compounds in the concentrates can have low oxidation,contributing to these desirable properties.

(1) DHA/EPA

Exemplary of non-polar ingredients that contain one or more omega-3fatty acids, which can be used in the provided concentrates, e.g.,pre-emulsion concentrates and liquid nanoemulsion concentrates, areingredients containing DHA and/or EPA, for example, marine oil, e.g.,fish oil, krill oil and algae oil. Any oil containing DHA and/or EPA canbe used. In one example, the non-polar ingredient contains between 10%or about 10% and 40% or about 40% DHA. In another example, the non-polaringredient contains between 25% or about 25% and 45% or about 45% DHA.In another example, the non-polar ingredient contains at least 60% orabout 60%, by weight (w/w), DHA, for example, at least 65% or about 65%,at least 70% or about 70%, at least 75% or about 75%, at least 80% orabout 80%, at least 85% or about 85%, or at least 90% or about 90%, byweight (w/w), DHA. In another example, the non-polar ingredient containsbetween 5% or about 5% and 15% or about 15% EPA, for example, 5, 6, 7,8, 9, 10, 11, 12, 13, 14 or 15%, by weight (w/w), EPA. In anotherexample, the non-polar ingredient comprises not more than 10% or about10% EPA or less than 10% or about 10%, EPA. In another example, thenon-polar ingredient contains DHA and EPA, for example, DHA representingat least 20% or about 20%, by weight, of the non-polar ingredient andEPA representing not more than 13% or about 13% of the non-polaringredient, for example, not more than 10% or about 10%, by weight, ofthe non-polar ingredient. In another example, the non-polar ingredientcontains DHA, representing at least 35% or about 35% of the non-polaringredient and EPA representing not more than 13% or about 13% of thenon-polar ingredient, for example, not more than 10% or about 10% of thenon-polar ingredient. In another example, the non-polar ingredientcontains DHA and EPA, for example, DHA representing at least 70% orabout 70% of the non-polar ingredient and EPA representing not more than13% or about 13% of the non-polar ingredient, for example, not more than10% or about 10% of the non-polar ingredient. In one example, thenon-polar ingredient contains DHA and EPA, for example, the total of DHAand EPA represents at least 30% or about 30% of the non-polaringredient. In another example, the non-polar ingredient contains DHAand EPA, for example, the total of DHA and EPA represents at least 61%or about 61% of the non-polar ingredient.

(i) Fish Oils

Exemplary of the PUFA-containing non-polar ingredients that can be usedin the provided concentrates, e.g. pre-emulsion concentrates and liquidnanoemulsion concentrates, are oils derived from fish which contain DHA,EPA or both DHA and EPA. Particularly, cold water marine fish are aknown source of omega-3 fatty acids (U.S. Pat. No. 4,670,285). Suitablefish oils containing DHA, EPA or both DHA and EPA can be obtained fromany of a number of commercial sources, for example, fish oils availablefrom Jedwards International, Inc., any of which can be used with theprovided compositions.

Fish oils typically are extracted from fish tissue, for example, frozenfish tissue. For example, the fish oil can be a tasteless fish oil, forexample, a cod liver oil, which has been isolated from fish, forexample, from cod liver, and then refined and deodorized, or in someother way treated so its taste becomes neutral, such as described inInternational Publication Nos. WO 00/23545 and WO 2004/098311. In oneexample, these fish oils are isolated from frozen fish tissue by aprocess that minimizes oxidation. Exemplary of such a tasteless fish oilis a fish oil sold under the trademark Denomega™ 100 (BorregaardIngredients, Sarpsborg, Norway; distributed by Denomega Nutritional OilsAS, Boulder, Colo.). Typically, the tasteless fish oil, for example, codliver oil, contains between or about between 25% and 35% omega-3 fattyacids, for example, 34% omega-3 fatty acids. In one example, the fishoil, for example, the Denomega™ 100 oil, contains 13% or about 13% DHAand 13% or about 13% EPA.

Also exemplary of the fish oils that can be included in the providedconcentrates are fish oils containing high amounts of omega-3 fattyacids, for example, high amounts of DHA. One example of such a fish oilcontains at least or about at least 85% DHA, typically greater than 85%DHA, and at least or about at least 90% omega-3 fatty acids, typicallygreater than 90% omega-3 fatty acids. In another example, the fish oilcan contain 98% PUFA, 89% omega-3 fatty acids, about 70% DHA, about 10%EPA, 8.9% omega-6 fatty acids and 0.7% omega-9 fatty acids.

Exemplary of a fish oil containing high amounts of omega-3 fatty acidsthat can be used as the non-polar ingredient in the providedconcentrates is an omega-3 fish oil EE (O3C Nutraceuticals; supplied byJedwards International Inc., Quincy, Mass.), which contains 89% omega-3fatty acids, 8.9% omega-6 fatty acids, 0.7% omega-9 fatty acids, 0.1%saturated fatty acids, 1.0% monounsaturated fatty acids, 74.5%docosahexanoic (DHA) fatty acids, 9.3% eicosapentaenoic (EPA) fattyacids and 98% polyunsaturated fatty acids (PUFA). This fish oil alsocontains 0.1% (16:0) palmitic acid, 0.1% (16:1 ω7) palmitoleic acid,0.1% (18:0) stearic acid, 0.6% (18:1 ω9) oleic acid, 0.1% (18:1 ω 7)oleic acid, 0.3% (18:2 ω6) linoleic acid, 0.2% (18:3 ω3) linolenic acid,0.2% (18:4 ω 3) octadecatetraenoic acid, 0.1% (20:1 ω 9) eicosanoicacid, 0.1% (20:2 ω6) eicosadienoic acid, 0.2% (20:3 ω6) eicosatrienoicacid, 2.4% (20:4 ω6) arachidonic acid, 0.6% (20:4 ω3) arachidonic acid,0.1% (22:1 ω11) erucic acid, 0.6% (21:5 ω3) uncosapentaenoic acid, 0.5%(22:4 ω6) docosatetraenoic acid, 5.4% (22:5 ω6) docosapentaenoic acid,3.6% (22:5 ω3) docosapentaenoic acid and 0.9% other fatty acids.

Also exemplary of a fish oil containing high amounts of omega-3 fattyacids that can be used in the provided concentrates is Omega Concentrate85 DHA TG Ultra (O3C Nutraceuticals AS, Oslo, Norway), which containsgreater than 85% DHA (C22:6n-3) and greater than 90% total omega-3 fattyacids and is isolated from fatty fish species in the Eugraulidae,Clupeidae and Scombridae families. This fish oil is produced bypurifying and concentrating the oils from these fish with gentletechnologies to increase the concentration of omega-3 fatty acid DHA.Any fish oil containing DHA and/or EPA can be used as the non-polaringredient in the provided compositions. Also exemplary of the fish oilsare other fish oils made by O3C Nutraceuticals, AS and other fish oilssupplied by Jedwards International, Inc.

Any fish oil containing DHA and/or EPA can be used as the non-polaringredient in the provided concentrates. Exemplary of the fish oils thatcan be included in the provided compositions is Eterna™ Omegasource™ Oil(supplied by Hormel Foods Specialty Products Division, Austin, Minn.),which contains at least 30% omega-3 fatty acids (DHA, EPA and ALA), isodorless, virtually free of cholesterol and bland in flavor. This fishoil contains about 28% DHA and EPA, typically 17% EPA and 11% DHA, andadditionally contains 4.5% omega-6 fatty acids. Also exemplary of thefish oils that can be included in the provided compositions are Omega 30TG Food Grade (Non-GMO) MEG-3™ Fish Oil (supplied by Ocean NutritionCanada, Dartmouth, Nova Scotia, Canada), a kosher fish oil whichcontains about 30% DHA/EPA and Marinol C-38 (supplied by Lipid NutritionB.V., Channahon, Ill.), which contains about 52% omega-3 fatty acids,including at least 38% DHA/EPA, more specifically includes about 22% EPAand 14% DHA. Also exemplary of fish oils are Marinol D-40 (supplied byLipid Nutrition B.V., Channahon, Ill.), which contains about 40% DHA and7% EPA; omega-3 fish oil 70TG that is 61% by weight DHA/EPA; fish oilssold by GC Rieber Oils (Kristiansund, Norway) that contain 30% or 65%DHA; ONC TG fish oil sold by Ocean Nutrition Canada (Dartmouth, NovaScotia); Omevital™ 30% MP Gold, a fish oil that contains 30% DHA/EPA(Cognis, Monheim am Rhein, North Rhine-Westphalia, Germany); and a fishoil containing 60% DHA (sold by FINA LLC, Cincinnati, Ohio). Alsoexemplary of the fish oils are krill oils, such as those made accordingto International Publication No. WO 2007/080515.

(ii) Algae Oil

Also exemplary of non-polar ingredients containing omega-3 PUFAs,particularly DHA (and optionally EPA), that can be used as the non-polaringredient in the provided concentrates, e.g., pre-emulsion concentratesand liquid nanoemulsion concentrates, are oils derived frommicroorganisms, for example, oils derived from marine dinoflagellates,such as microalgae, e.g., Crypthecodinium sp, particularlyCrypthecodinium cohnii. Microalgae oils, like fish oils, are anexcellent source of omega-3 fatty acids, particularly DHA (U.S. Pat.Nos. 5,397,591; 5,407,957; 5,492,938; and 5,711,983). Exemplary of oilsderived from microalgae are the oils disclosed in (and oils madeaccording to the methods described in) U.S. Pat. Nos. 5,397,591;5,407,957; 5,492,938; and 5,711,983 and U.S. Publication No.2007/0166411, including DHASCO® and DHASCO-S® (Martek BiosciencesCorporation).

For example, U.S. Pat. No. 5,397,591 describes, inter alia, single-celledible oils (algae oils) (and methods for making the oils), whichcontain at least 70% triglycerides, which contain about 20-35% DHA andlack EPA, isolated from Crypthecodinium cohnii, preferably containingmore than 70% triglycerides, having 15-20% myristic acid; 20-25%palmitic acid; 10-15% oleic acid; 30-40% DHA; and 0-10% othertriglycerides. U.S. Pat. No. 5,407,957 describes, inter alia, algae oils(and methods for making the oils) derived from Crypthecodinium cohnii,preferably containing greater than about 90% triglycerides, at least 35%DHA, by weight (w/w), in one example, having 15-20% myristic acid;20-25% palmitic acid; 10-15% oleic acid; 40-45% DHA; and 0-5% otheroils. U.S. Pat. No. 5,492,938 describes, inter alia, single cell edibleoils (and methods for making the oils) containing at least 70%triglycerides, which contain about 20-35% DHA and lack EPA, isolatedfrom Crypthecodinium cohnii, in one example containing more than 70%triglycerides, having 15-20% myristic acid; 20-25% palmitic acid; 10-15%oleic acid; 30-40% DHA; and 0-10% other triglycerides. U.S. Pat. No.5,711,983 describes, inter alia, single cell edible oils (and methodsfor making the oils) containing at least 70% triglycerides, whichcontain about 20-35% DHA and lack EPA, isolated from Crypthecodiniumcohnii, in one example, containing more than 70% triglycerides, having15-20% myristic acid; 20-25% palmitic acid; 10-15% oleic acid; 30-40%DHA; and 0-10% other triglycerides.

Also exemplary of suitable microalgae oils are those disclosed, forexample, in U.S. Pat. No. 6,977,166 and U.S. Publication No. US2004/0072330. Any oil derived from dinoflagellate, for example,microalgae, which contains DHA, and optionally EPA, is suitable as analgae oil for use with the provided compositions, for example, V-Purealgae oil (Water4Life, Switzerland), which contains EPA and DHA, andMartek DHA™-S (supplied by Martek Biosciences Corporation, Columbia,Md.), derived from the marine alga Schizochytrium sp., containing notless than 35% DHA and 16.1% (22:5 ω6) docosapentaenoic acid, 1.3% (20:5ω3) eicosapentaenoic acid, 0.6% (20:4 ω6) arachidonic acid, 1.6% (18:2ω6) linoleic acid, 16.9% (18:1 ω9) oleic acid and 19.8% other fattyacids.

(2) Flax Seed Oil—Omega 3 (ALA)

Also exemplary of the omega-3 containing non-polar ingredients used inthe provided concentrates, e.g., pre-emulsion concentrates and liquidnanoemulsion concentrates, is flaxseed oil (linseed oil). Flaxseed oils,which are good sources of omega-3 fatty acids, particularlyalpha-linolenic acid, have been used as nutritional supplements.Flaxseed oils are produced by pressing the flax seed and refining theoil from the flax seeds. Exemplary of flaxseed oil that can be used asthe non-polar ingredient in the provided compositions is flaxseed oilderived from Linum usitatissimum L. Exemplary of flaxseed oils suitablefor use in the concentrates provided herein include flaxseed oilsupplied by Sanmark LLC (Greensboro, N.C.; Sanmark Limited, Dalian,Liaoning Province, China), which contains not less than (NLT) 50% C18:3alpha-linolenic acid, and further contains other fatty acids, forexample, 3-8% C16:0 palmitic acid, 2-8% C18:0 stearic acid, 11-24% C18:1oleic acid, 11-24% C18:2 linoleic acid and 0-3% other fatty acids. Alsoexemplary of suitable flaxseed oil is a flaxseed oil containing 6%palmitic acid, 2.5% stearic acid, 0.5% arachidic acid, 19% oleic acid,24.1% linoleic acid, 47.4% linolenic acid, and 0.5% other fatty acids.The fatty acid composition of flaxseed oil can vary. Any flaxseed oilcan be used as the non-polar ingredient in the provided compositions.For example, the flaxseed oil can contain at least or about at least50%, at least or about at least 65%, or at least or about at least 70%alpha-linolenic acid. Exemplary of a flaxseed containing greater than65% linolenic acid content (of total fatty acid content), for example,70-80% or 70-75%, is the flaxseed described in U.S. Pat. No. 6,870,077.

(b) Omega-6 Compounds

Also exemplary of the non-polar ingredients used in the providedconcentrates, e.g., pre-emulsion concentrates and liquid nanoemulsionconcentrates, are ingredients containing omega-6 PUFAs, for example,gamma-linolenic acid (GLA), for example, borage oil and evening primrose(Oenothera biennis) oil, blackcurrant seed oil, hemp seed oil, fungaloil and spirulina extract. Any oil containing omega-6 fatty acids can beused in the provided compositions.

Exemplary of the omega-6 containing non-polar ingredients areingredients containing GLA, for example, borage oil. GLA is an omega-6PUFA, which primarily is derived from vegetable oils, for example,evening primrose (Oenothera biennis) oil, blackcurrant seed oil, hempseed oil, and spirulina extract. GLA has been used as a nutritionalsupplement. It has been proposed that GLA has a role in treating variouschronic diseases and in particular that it has anti-inflammatory effects(Fan and Chapkin (1998) J. Nutr. 128(9):1411-1414). In one example, thenon-polar ingredient contains at least or about at least 22 wt % of GLA,for example, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 50, 60 wt % or more, by weight, of GLA.

Borage (Borago officinalis), also known as “starflower,” is an herb withseeds containing high amounts of GLA. Exemplary of borage oils that canbe used as a non-polar ingredient in the provided compositions areborage oils supplied by Sanmark LLC (Greensboro, N.C.; Sanmark Limited,Dalian, Liaoning Province, China), derived by pressing and isolating oilfrom the seeds of Borago officinalis L. This oil contains not less than(NLT) 22% C18:3 gamma-linolenic acid (GLA), between 9 and 12% C16:0palmitic acid, between 3% and 5% C18:0 stearic acid, between 15% and 20%C18:1 oleic acid, between 35% and 42% C18:2 linoleic acid, between 3%and 5% C20:1 ocosenoic acid, between 1% and 4% C22:1 docosenoic acid andbetween 0% and 4% other fatty acids. Other borage oils can be used.Other GLA-containing oils also can be used as the non-polar ingredient.

(c) Saw Palmetto Extract

Also exemplary of the non-polar ingredients used in the providedconcentrates, e.g., pre-emulsion concentrates and liquid nanoemulsionconcentrates, is saw palmetto extract, a lipophilic extract of the ripeberries of the American dwarf palm (also called Serenoa repens or Sabalserrulata), which has been used to treat genitourinary and otherdiseases and to enhance sperm production, breast size and libido, as amild diuretic, a nerve sedative, an expectorant and a digestive tracttonic, and particularly to treat benign prostate hyperplasia (BHP)(Ernst (2002) Acad. Clin. 136:42-53; and Gordon and Shaughnessy (2003)Comp. Alt. Med. 76(6):1281-1283). Saw palmetto extract is commerciallyavailable from a number of sources. Any saw palmetto lipid extract canbe used in the provided concentrates. Exemplary of the saw palmettoextract that can be used in the provided concentrates is Saw Palmetto,Lipophilic Extract, commercially available from Natural Medicinals, Inc.(Felda, Fla.). This saw palmetto lipophilic extract is carbon dioxideextracted and, in one example, contains 85.9% total fatty acids,including 0.8% caproic acid, 2% caprylic acid, 2.4% capric acid, 27.%lauric acid, 10.3% myristic acid, 8.1% palmitic acid, 0.2% palmitoleicacid, 2% stearic acid, 26.7% oleic acid, 4.9% linoleic acid, 0.7%linolenic acid, 0.42% phytosterols, including 0.42% beta sitosterol,0.09% campesterol, 0.03% stigmasterol; and 0.2% moisture. Other sourcesof saw palmetto extract can be used.

(d) Conjugated Linoleic Acid (CLA)

Also exemplary of the PUFA non-polar ingredients that can be used in theprovided concentrates, e.g., pre-emulsion concentrates and liquidnanoemulsion concentrates, are non-polar ingredients containingconjugated fatty acids. Conjugated fatty acids are PUFAs with two ormore conjugated double bonds. Conjugated fatty acids can be used asnutritional supplements. Exemplary of the non-polar ingredientscontaining conjugated fatty acids are compounds containing conjugatedlinoleic acid (CLA), for example, 18:2 ω7 and 18:2 ω6; conjugatedlinolenic acid, for example, 18:3ω6 and 18:3ω5; and other conjugatedfatty acids, for example, 18:3 ω3, 18:4 ω3 and 20:5 ω6. CLA refers to afamily of linoleic acid isomers found primarily in meat and dairyproducts of ruminants. Typically, the CLA compounds contain a mixture ofdifferent CLA isomers, for example, C18:2 CLA c9, t11, CLA t10, c12 andother CLA isomers. Exemplary of the CLA that can be used as a non-polaringredient in the provided compositions is CLA (70%) commerciallyavailable from Sanmark, LTD (Dalian, Liaoning Province, China; productcode 01057-A80). This CLA is a clear white to pale yellow oil and hasthe following fatty acid composition: NMT (not more than) 9.0% C16:0palmitic acid, NMT 4.0% stearic acid, NMT 15.0% C18:1 oleic acid, NMT3.0% C18:2 linoleic acid, NLT (not less than) 80% C18:2 CLA (includingthe following isomers: NLT 37.5% C18:2 CLA c9, t11, 37.5% C18:2 CLA t10,c12, and NMT 5.0% other CLA isomers); and NMT 5.0% other fatty acids.Another exemplary CLA compound is a CLA that contains 74.5% CLA(Clarinol® CLA, Stepan Lipid Nutrition, Maywood, N.J.). OtherCLA-containing compounds can be used.

ii. Coenzyme Q Compounds

Exemplary of the non-polar ingredients are ingredients that are orcontain the non-polar compound coenzyme Q, for example, coenzyme Q10(also called coQ10, ubiquinone, ubidecarenone, ubiquinol and vitaminQ10). Coenzyme Q compounds are benzoquinone compounds containingisoprenyl units. The number of isoprenyl units in each of the differentCoQ species is indicated with a number following CoQ. For example, coQ10contains 10 isoprenyl units. Coenzyme Q10 is a predominant coenzyme Qspecies.

Coenzyme Q can exist in two different forms: an oxidized form and areduced form. When the oxidized form of a coenzyme Q species is reducedby one equivalent, it becomes a ubisemiquinone, denoted QH, whichcontains a free radical on one of the oxygens in the benzene ring of thebenzoquinone. Both oxidized and reduced coenzyme Q-containing compoundscan be used as non-polar ingredients in the provided compositions.

Exemplary of the coenzyme Q-containing non-polar ingredients that can beused in the provided concentrates, e.g., pre-emulsion concentrates andliquid nanoemulsion concentrates, are non-polar ingredients containingcoenzyme Q10 (also called coQ10, ubiquinone, ubidecarenone, ubiquinoland vitamin Q10), a benzoquinone compound that contains 10 isoprenoidunits. The “Q” in the name refers to quinone and the 10 refers to thenumber of isoprenoid units. CoQ10 typically refers to the oxidized formof coQ10, which also is referred to as ubidecarenone, as opposed to thereduced form of coQ10. Both the reduced and oxidized forms of coQ10 areexemplary of the coenzyme Q species that can be used as non-polaringredients in the provided concentrates.

CoQ10 has electron-transfer ability and is present in cellularmembranes, such as those of the endoplasmic reticulum, peroxisomes,lysosomes, vesicles and the mitochondria. A decrease in natural coQ10synthesis has been observed in sick and elderly people. Because of thisobservation and its potent antioxidant properties, coQ10 is used as adietary supplement and a treatment for diseases such as cancer and heartdisease. CoQ10, however, exhibits relatively poor bioavailability.

CoQ10 containing compounds are available commercially. Any coQ10compound or reduced coQ10 compound can be used with the providedconcentrates, e.g., pre-emulsion concentrates and liquid nanoemulsionconcentrates. Exemplary of the coQ10 compounds that can be used arecoenzyme Q10 compounds containing greater than 98% or greater than about98% ubidecarenone, for example, the compound sold under the name KanekaQ10™ (USP Ubidecarenone) by Kaneka Nutrients, L.P. (Pasadena, Tex.). Thecompound sold under the name Kaneka Q10™ is fermented entirely fromyeast and is identical to the body's own coQ10 and free from the cisisomer found in some synthetically produced coQ10 compounds. Any coQ10compound can be used in the provided concentrates.

iii. Phytochemical-Containing Non-Polar Ingredients

Exemplary of the non-polar ingredients that are or contain non-polarcompounds in the provided compositions are phytochemical-containingcompounds, for example, phytosterols (plant sterols), phytoestrogens,for example, genistein and daidzein, flavonoids, for example,isoflavones, for example, soy isoflavones, phytoalexins, for example,resveratrol (trans-3,5,4′-trihydroxystilbene) and red clover extract.

Typically, phytochemical-containing ingredients are added to thecompositions in amounts such that when diluted in a beverage, oneserving of the beverage provides between at or about 0.5 and at or about10 mg, typically, between at or about 1 and at or about 10 mg, betweenat or about 1 and at or about 5 mg, for example, at or about 0.5, at orabout 1, at or about 2, at or about 3, at or about 4, at or about 5 mg,at or about 6 mg, at or about 7 mg, at or about 8 mg, at or about 9 mgor at or about 10 mg phytochemical-containing compound, for examplephytochemical-containing compound, per serving of the beverage, such asfor example, 8 ounces of a beverage.

(a) Phytosterols

Exemplary of the phytochemical-containing compounds that containnon-polar ingredients in the provided compositions are phytosterols(plant sterols). Plant sterols are structurally similar to cholesteroland have been found to reduce the absorption of dietary cholesterol,which can affect the levels of serum cholesterol. According to the U.S.Food and Drug Administration (FDA), two servings per day, eachcontaining 0.4 grams of plant sterols, for a total daily intake of atleast 0.8 grams, as part of a diet low in saturated fat and cholesterol,is reported to reduce the risk of heart disease. Thus, plant sterols areused in nutritional supplements.

Phytosterol non-polar ingredients are typically added to thecompositions in amounts such that when diluted in a beverage, oneserving of the beverage provides between at or about 100 and at or about1000 mg, typically between at or about 100 and at or about 500 mg,between at or about 100 and at or about 800 mg, between at or about 300and at or about 500 mg, between at or about 300 and at or about 800 mg,between at or about 500 and at or about 1000 mg, for example, at orabout 100, at or about 200, at or about 300, at or about 400, at orabout 500, at or about 600, at or about 700, at or about 800, at orabout 900 or at or about 1000 mg phytosterols, per serving of thebeverage, such as for example, 8 ounces of a beverage.

Any phytosterol-containing compound can be used as a non-polaringredient in the provided compositions. Exemplary of thephytosterol-containing compounds that can be used as non-polaringredients in the provided compositions are compounds containing plantsterols, for example, the compound sold under the name CardioAid™,distributed by B&D Nutrition and manufactured by ADM Natural Health andNutrition, Decatur, Ill. This compound contains kosher, pareve, andhalal plant sterols that are produced under current food GMPs. Thesterols are PCR negative and the material is derived from geneticallymodified organisms (GMOs). This phytosterol compound contains a minimumof 95% plant sterols, which can include up to 5 plant sterols. Thecompound can contain, for example, 40-58% beta sitosterol, 20-30%campesterol, 14-22% stigmasterol, 0-6% brassicasterol and 0.5%sitostanol. The compound further can contain tocopherols, for example,0-15 mg/g tocopherols. The compound is tested and is negative formicroorganisms, such as Salmonella, E. coli and Staphylococcus aureus.

(b) Resveratrol

Exemplary of the phytochemical-containing compounds used as non-polaringredients in the provided compositions is resveratrol. Resveratrol, ortrans-resveratrol (trans-3,5,4′-trihydroxystilbene), is a phytoalexinthat is naturally produced by several plants, such as the Japaneseknotweed, and also is found in the skin and seeds of grapes, numerousberries, including mulberry, blueberries, bilberries and cranberries,and in peanuts. This polyphenolic compound can act as an antioxidant andadditionally aid in cancer prevention and reduction of cardiovasculardisease.

Any resveratrol-containing compound can be used as a non-polaringredient in the provided compositions. Exemplary of theresveratrol-containing compounds that can be used as non-polaringredients in the provided compositions are compounds containingtrans-resveratrol, for example the compounds sold under the nameReserveNature™, sold by Jiaherb, Shaanxi, China. This compound containstrans-resveratrol from the botanical source Polygonum cuspidatum(Japanese knotweed). This resveratrol compound contains a minimum of98.5% trans resveratrol and does not contain emodin. The compound istested and is negative for microorganisms, such as Salmonella, E. coli,yeast and mold.

iv. Carotenoid-Containing Compounds

Exemplary of the non-polar ingredients that are or contain non-polarcompounds and are use in the provided compositions arecarotenoid-containing ingredient, for example, carotenoids, includinghydrocarbons (carotenes) and oxygenated, alcoholic derivatives ofhydrocarbons (xanthophylls), for example, beta carotene, mixedcarotenoids complex, lutein, zeaxanthin, cryptoxanthin, for example,beta-cryptoxanthin, lycopene, beta carotene, mixed carotenoids complex,astaxanthin, bixin, canthaxanthin, capsanthin, capsorubin,apo-carotenal, beta-12′-apo-carotenal, “carotene” (mixture of alpha andbeta-carotene), gamma carotene, ciolerythrin and esters of hydroxyl- orcarboxyl-containing members thereof. Carotenoids are efficientfree-radical scavengers, or anti-oxidants, and are capable of enhancingthe vertebrate immune system.

Typically, carotenoid-containing compounds are used in the providedcompositions within a concentration range of between 0% or about 0% and10% or about 10%, typically between 0% or about 0% and 5% or about 5%,for example, at or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, w/w,of the beverage composition.

(a) Carotenes

Exemplary of the carotenoid-containing compounds used as non-polaringredients in the provided beverage compositions are carotenes, forexample, alpha-carotene, beta-carotene and lycopene. Anycarotene-containing compound can be used as a non-polar ingredient inthe provided compositions. Exemplary of the carotene-containingcompounds that can be used as non-polar ingredients in the providedcompositions is lycopene, sold by Zhejiang Medicine CO., LTD, XinchangPharmaceutical Factory, Xinchang, China, a purple or red crystallinepowder containing not less than 70% all E-lycopene, not more than 23%5-Z-lycopene and not more than 9% related substances.

(b) Xanthophylls

Exemplary of the carotenoid-containing compounds used in the providedcompositions are xanthophylls, for example, neoxanthin, violaxanthin, α-and β-cryptoxanthins, lutein and zeaxanthin. Xanthophylls, orphylloxanthins, are oxygen containing carotenoids that are typicallyyellow pigments. Any carotene-containing compound can be used as anon-polar ingredient in the provided compositions. Exemplary of thecarotene-containing compounds that can be used as non-polar ingredientsin the provided compositions are lutein and zeaxanthin, sold under thename Xanmax®-80 (Lutein crystals), by Katra Phytochem (India) PrivateLimited, Bangalore, India, containing 80% lutein and 4.5% zeaxanthin.

v. Micronutrient-Containing Compounds

Exemplary of the non-polar ingredients that are or contain non-polarcompounds that are used in the provided compositions aremicronutrient-containing ingredients, for example, vitamins, includingvitamins A, B, C, D, E and K, and corresponding provitamins and vitaminderivatives with an action resembling that of vitamin A, B, C, D, E orK, and alpha lipoic acid (thioctic acid), yerba mate, ginseng and ginkgobiloba.

(a) Vitamins

Exemplary of the vitamins used as non-polar ingredients in the providedcompositions are fat-soluble vitamins, for example, vitamins A, B, C, D,E and K, and corresponding provitamins and vitamin derivatives, such asesters with an action resembling that of vitamin A, B, C, D, E or K, forexample, retinol (vitamin A) and pharmaceutically acceptable derivativesthereof, for example, palmitate ester of retinol and other esters ofretinol, for example, vitamin A palmitate; B vitamins, for example,thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitaminB7), folic acid or folate (vitamin B9), and cyanocobalamin, cobalamin,or reduced forms of cobalamin (vitamin B12); calciferol (vitamin D) andits pharmaceutically acceptable derivatives thereof, for example, forexample, cholecalciferol (vitamin D3), and precursors of vitamin D;d-alpha tocopherol (vitamin E) and derivatives thereof, includingpharmaceutical derivatives thereof, for example, tocotrienols, d-alphatocopherol acetate and other esters of d-alpha tocopherol; and ascorbylpalmitate, a fat-soluble version of vitamin C.

Any vitamin can be used as a non-polar ingredient in the providedcompositions. Exemplary of the vitamins that can be used as non-polaringredients in the provided compositions are vitamin A palmitate, forexample, vitamin A palmitate containing 1.7 mIU/g, produced by DSMNutritional Products, Inc., Belvidere, N.J., and distributed throughStauber Performance Ingredients, Inc., Fullerton, Calif.; vitamin D3,for example, vitamin D3 in corn oil, containing about 1 mIU/g, producedby DSM Nutritional Products, Inc., Belvidere, N.J., and distributedthrough Stauber Performance Ingredients, Inc., Fullerton, Calif.;vitamin B12; vitamin B1; vitamin B3; vitamin B5; and vitamin B6.

Typically, vitamin non-polar ingredients are included in the providedcompositions within a concentration range of between 0.0001% or about0.0001% and 1% or about 1%, more typically between at or about 0.001%and at or about 0.1%, for example, at or about 0.0001%, 0.0005%,0.0008%, 0.0009%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%,0.03%, 0.04%, 0.05%, 0.1%, 0.5% or 1%, w/w, of the beverage composition.Vitamin non-polar ingredients are typically added to the beveragecompositions in amounts such that one serving of the beverage providesan amount of the vitamin that corresponds to the dietary referenceintakes. For example, vitamin A is added such that a serving of thebeverage provides between at or about 10 to at or about 2000 micrograms(mcg), for example, between at or about 20 to at or about 900 mcg, moretypically between at or about 40 to at or about 400 mcg of vitamin A perserving, for example, between at or about 40 and at or about 200 mcg, orbetween at or about 100 and at or about 400 mcg, or between at or about100 and at or about 300 mcg per serving. For example, the beveragecomposition can contain 40 or about 40, 50 or about 50, 60 or about 60,70 or about 70, 80 or about 80, 90 or about 90, 100 or about 100, 110 orabout 110, 120 or about 120, 130 or about 130, 140 or about 140, 150 orabout 150, 200 or about 200, 250 or about 250, 300 or about 300, 350 orabout 350, or 400 or about 400 mcg vitamin A per serving. In anotherexample, vitamin D3 is added such that a serving of the beveragecomposition provides between at or about 100 to at or about 2000International Units (IU), for example, between at or about 100 to at orabout 1000 IU, more typically, between at or about 400 and at or about800 IU, per serving, for example between at or about 400 and at or about600 or between at or about 500 and at or about 800, or between at orabout 600 and at or about 800 IU per serving. For example, the beveragecomposition can contain 400 or about 400, 450 or about 450, 500 or about500, 550 or about 550, 600 or about 600, 650 or about 650, 700 or about700, 750 or about 750 or 800 or about 800 IU vitamin D3 per serving. Inanother example, vitamin B12 is added such that a serving of thebeverage composition provides between at or about 1 and 12 mcg, such as1 or about 1, 2 or about 2, 2.4 or about 2.4, 3 or about 3, 4 or about4, 5 or about 5, 6 or about 6, 8 or about 8, 10 or about 10 or 12 orabout 12 mcg vitamin B12 per serving. In another example, vitamin B1 isadded such that a serving of the beverage composition provides betweenat or about 0.2 and 1.4 mg, such as 0.2 or about 0.2, 0.3 or about 0.3,0.4 or about 0.4, 0.5 or about 0.5, 0.6 or about 0.6, 0.7 or about 0.7,0.8 or about 0.8, 0.9 or about 0.9, 1.0 or about 1.0, 1.1 or about 1.1,1.2 or about 1.2, 1.3 or about 1.3 or 1.4 or about 1.4 mg vitamin B1 perserving. In another example, vitamin B3 is added such that a serving ofthe beverage composition provides between at or about 2 and 18 mg, suchas 2 or about 2, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about 6,7 or about 7, 8 or about 8, 9 or about 9, 10 or about 10, 11 or about11, 12 or about 12, 13 or about 13, 14 or about 14, 15 or about 15, 16or about 16, 17 or about 17 or 18 or about 18 mg vitamin B3 per serving.In another example, vitamin B5 is added such that a serving of thebeverage composition provides between at or about 1.7 and 7 mg, such as1.7 or about 1.7, 1.8 or about 1.8, 1.9 or about 1.9, 2 or about 2, 3 orabout 3, 4 or about 4, 5 or about 5, 6 or about 6 or 7 or about 7 mgvitamin B5 per serving. In another example, vitamin B6 is added suchthat a serving of the beverage composition provides between at or about0.1 and 2.0 mg, such as 0.1 or about 0.1, 0.2 or about 0.2, 0.3 or about0.3, 0.4 or about 0.4, 0.5 or about 0.5, 0.6 or about 0.6, 0.7 or about0.7, 0.8 or about 0.8, 0.9 or about 0.9, 1.0 or about 1.0, 1.1 or about1.1, 1.2 or about 1.2, 1.3 or about 1.3, 1.4 or about 1.4, 1.5 or about1.5, 1.6 or about 1.6, 1.7 or about 1.7, 1.8 or about 1.8, 1.9 or about1.9 or 2.0 or about 2.0 mg vitamin B6 per serving.

(b) Alpha-Lipoic Acid (Thioctic Acid)

The alpha lipoic acid non-polar ingredients include the alpha-lipoicacids sold by NutriChem Resources Company (Walnut, Calif.) and ZhejiangMedicines & Health Products Import & Export Co., Ltd (Hangzhou, China)and other alpha-lipoic acids. Typically, alpha-lipoic acid is used inthe provided compositions within a concentration range of between 0% orabout 0% and 10% or about 10%, typically between 0% or about 0% and 5%or about 5%, for example, at or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%or 10%, w/w, of the beverage composition.

vi. Boswellia Extracts

Exemplary of non-polar ingredients included in the compositions hereinare non-polar ingredients containing extracts of a Boswellia plant or aboswellic acid or derivative thereof. Extracts of the Boswellia familyof plants, including, for example, Boswellia serrata, exhibitanti-inflammatory, anti-arthritic and anti-ulcerogenic activity (see,e.g., U.S. Pat. No. 6,589,516). Extracts derived from Boswellia plantsand suitable for use in the pre-gel concentrates provided herein includeextracts derived from Boswellia cartenii, Boswellia frereana, Boswelliabhau-dajaina, Boswellia serrata, and Boswellia thurifera. The extractsderived from Boswellia plants can be gums, oleo-gums, resins, essentialoils and residues, or mixtures thereof. A typical extract of a Boswelliaplant suitable for use herein includes at least one boswellic acid, forexample, acetyl-11-keto-β-boswellic acid (AKBA). Exemplary of aBoswellia extract-containing compound that can be used as the non-polaringredient in the provided pre-gel concentrates is sold under thetrademark ApresFLEX®, which is a formulation that includes a Boswelliaserrata extract that contains acetyl-11-keto-β-boswellic acid (AKBA),sold by PLT Health Solutions, Morristown, N.J.

vii. Alkaloids

Exemplary of non-polar ingredients in the provided pre-gel concentratesare non-polar ingredients that are or contain an alkaloid, for example,any edible or food-approved alkaloid. Exemplary suitable alkaloidsinclude, but are not limited to, caffeine, synephrine, andγ-aminobutyric acid (GABA) derivatives, e.g., 4-amino-3-phenylbutyricacid (i.e., phenibut). Other exemplary non-polar ingredients containingalkaloids include herbal extracts, medicinal extracts and compounds fromplants and drugs. Suitable alkaloids for inclusion in the providedpre-gel concentrates are a matter of design choice and well within theskill of the skilled artisan.

The amount of alkaloid depends upon the desired or intended dosage andthe particular compound. For example, the amount of alkaloid, e.g.,caffeine, included in the provided beverage compositions is typicallybetween or between about 0.01% and 10%, by weight, of the composition,for example, between at or about 0.01% and 9%, between at or about 0.01%and at or about 8%, between at or about 0.01% and at or about 7%,between at or about 0.01% and at or about 6%, between at or about 0.01%and at or about 5%, between at or about 0.01% and at or about 4%,between at or about 0.1% and at or about 3%, between at or about 0.1%and at or about 6%, between at or about 0.1% and at or about 5%, betweenat or about 0.1% and at or about 4%, between at or about 0.1% and at orabout 3%, between at or about 0.1% and at or about 2%, between at orabout 0.1% and at or about 1%, between at or about 0.5% and at or about7%, between at or about 0.5% and at or about 6%, between at or about0.5% and at or about 5%, between at or about 0.5% and at or about 4%,between at or about 0.5% and at or about 3%, between at or about 0.5%and at or about 2%, between at or about 0.5% and at or about 1%, betweenat or about 1% and at or about 7%, between at or about 1% and at orabout 6%, between at or about 1% and at or about 5%, between at or about1% and at or about 4%, between at or about 1% and at or about 3%,between at or about 1% and at or about 2%, between at or about 2% and ator about 7%, between at or about 2% and at or about 5%, between at orabout 2% and at or about 4%, between at or about 3% and at or about 7%,between at or about 3% and at or about 5%, between at or about 4% and ator about 7%, between at or about 6% and at or about 7%, between at orabout 5% and at or about 7%, or between at or about 5% and at or about6%, by weight, of the beverage composition. In some examples, the amountof alkaloid used in the provided beverage compositions is less than 7%or about 7%, typically less than 5% or about 5%, for example at or about0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%,1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%,3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%,5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.2%,6.5%, 6.7%, or 7%, by weight, of the beverage composition.

The alkaloid-containing non-polar ingredients include caffeine that isadded in the form of caffeine anhydrous, such as the Caffeine Anhydrouspowder (white, crystalline powder), sold by Pacific RainbowInternational, Inc., City of Industry, Calif., which is a whitecrystalline powder containing caffeine anhydrous. The amount ofalkaloid, e.g., caffeine, in the composition can be between at or about0% and at or about 50%, by weight, of the composition, and typically isbetween at or about 0% and at or about 25%, such as at or about 0% andat or about 10%, or between at or about 0% and at or about 5%, e.g., ator about 0%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%,0.7%, 0.8%, 0.9%, 1% 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%,9%, or 10%, such as between at or about 0% and at or about 3%, byweight, of the composition, e.g., between at or about 0% and 2%, e.g.,at or about 2%, by weight, of the composition, or is less than 5%, byweight, of the composition, e.g., at or about 5, 4, 3, 2 or 1%, byweight, of the composition, or less. In one example, the compositioncontains at or about 2%, by weight, caffeine. In another example, thecomposition contains between at or about 1 mg and at or about 500 mgcaffeine per mL or per serving, such as a 4 mL serving of thecomposition, e.g., at or about 200, 150, 125, 100, 80, 75, 50 or 25milligrams (mg) caffeine per serving of the composition, e.g., per 4 mLof the composition.

Other exemplary ingredients including alkaloids include herbal extracts,medicinal extracts and compounds from plants and drugs. Example 10 belowdescribes additional exemplary non-polar ingredients.

viii. Cannabinoids

Cannabinoids and cannabinoid-containing compounds are exemplary ofnon-polar ingredients that can be included the compositions providedherein. Cannabinoids include phytocannabinoids (found in the Cannabissativa plant and some other plants), endocannabinoids (producednaturally in the body by humans and animals), and syntheticcannabinoids. Cannabinoids that can be included in the pre-gelconcentrates provided herein can be natural cannabinoids, syntheticcannabinoids, semi-synthetic cannabinoids, or mixtures thereof. Actualor potential therapeutic applications for cannabinoids include thetreatment of multiple sclerosis and other forms of muscular spasm,migraine headache, glaucoma, asthma, inflammation, insomnia, high bloodpressure, nausea and vomiting, and the stimulation of appetite. Otherpotential therapeutic applications include the use of cannabinoids asoxytoxic, anxiolytic, anti-convulsive, anti-depressive, anti-psychotic,and anti-cancer agents.

Exemplary phytocannabinoids derived from the Cannabis sativa plant(commonly known as marijuana) are the terpenophenolic compoundsΔ⁹-tetrahydrocannabinol (THC), Δ⁸-tetrahydrocannabinol (Δ⁸-THC) andother compounds structurally related to THC, cannabidiol (CBD),cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN),cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV),cannabidivarin (CBDV), cannabielsoin (CBE), cannabicitran (CBT),cannabinodiol (CBDL), cannabichromevarin (CBCV), cannabigerovarin(CBGV), cannabigerol monoethyl ether (CBGM), and mixtures andderivatives thereof, for example, nabiximols (Sativex®), a mixture ofTHC and CBD. Suitable phytocannabinoids also include those derived fromplants other than Cannabis sativa, such as, for example, lipophilicalkamides (alkylamides) derived from Echinacea plants, and othercannabinoids derived from plants including, but not limited to,Echinacea purpurea, Echinacea angustifolia, Echinacea pallida, Acmellaoleracea, Helichrysum umbraculigerum, and Radula marginata plants.

Endogenous cannabinoids are lipid-like substances produced in the brainand peripheral tissues that bind to and activate cannabinoid receptorspresent in the cell membrane, including, but not limited to,arachidonate acid-based lipids such as anandamide(N-arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG),noladin ether (2-arachidonyl glyceryl ether), N-arachidonoyl dopamine(NADA), and virodhamine (OAE).

Synthetic cannabinoids are among the cannabinoids that can be includedas non-polar ingredients. Synthetic cannabinoids include any compoundhaving a cannabinoid-like structure or that produces effects similar tothose of cannabinoids that is manufactured using chemical means,including, for example, synthetic Δ⁹-THC; dronabinol (Marinol®;(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol);nabilone (Cesamet™;(±)-trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one); dexanabinol((6aS,10aS)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol); ajulemic acid(Resunab™;(6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo(b,d)pyran-9-carboxylicacid); cannabinor((E)-4-(2-((1R,2R,5R)-6,6-dimethyl-4-oxobicyclo[3.1.1]heptan-2-yl)-3-hydroxy-5-(2-methyloctan-2-yl)phenoxy)-4-oxobut-2-enoicacid); HU 308([(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol);rimonabant (Acomplia™;5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide);taranabant (MK-0364;N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-butanyl]-2-methyl-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}propanamide);levonantradol([(6S,6aR,9R,10aR)-9-hydroxy-6-methyl-3-[(2R)-5-phenylpentan-2-yl]oxy-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-1-yl]acetate); WIN55212-2((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone); HU 331(3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex-2-en-1-yl]-5-pentyl-1,4-benzoquinone);and any other compound having a cannabinoid-based structure or thatproduces effects similar to those of cannabinoids that is manufacturedusing chemical means.

ix. Hops-Containing Compounds

Exemplary of non-polar ingredients that can be included in the providedcompositions are ingredients that contain hops (Humulus lupulus L.),including ingredients isolated or derived from hops, such as extracts ofhops cones, for example, hops oils, hops resins or hops resinderivatives, hops acids or hops acid derivatives, or mixtures thereof.Hops oils include, but are not limited to, humulene, beta-caryophyllene,mycrene, farnescene, gamma-cadinene, alpha-selinene, and alpha-cadinene.Hops contain alpha-acids, such as humulone (α-lupulic acid), cohumulone,adhumulone, hulupone, and isoprehumulone, and beta-acids, such aslupulone, colupulone, adlupulone, tetrahydroisohumulone, andhexahydrocolupulone. Both alpha- and beta-acids have demonstratedantibacterial, antioxidant, and antiinflammatory properties. Anexemplary non-polar ingredient containing hops is sold under thetrademark Perluxan™, and that is a compound containing a supercriticalextract of hops cones that includes a minimum of 30% alpha-acids(including humulone, cohumulone, adhumulone, iso-cohumulone andiso-adhumulone) and 10% beta-acids (including lupulone and colupulone),such as sold by Pharmachem Laboratories, Kearny, N.J.

x. Antioxidants

Exemplary of non-polar ingredients that can be included in thecompositions provided herein are ingredients that contain an antioxidantor have antioxidant properties, for example, a molecule that is capableof inhibiting the oxidation of other molecules. Antioxidants includemolecules that scavenge free radicals. Suitable antioxidants includethose that are used as ingredients in dietary supplements. Theantioxidant can be a natural antioxidant or a synthetic antioxidant.

Examples of antioxidants include, but are not limited to hormones,carotenoids, carotenoid terpenoids, non-carotenoid terpenoids,flavonoids, flavonoid polyphenolics (e.g., bioflavonoids), flavonols,flavones, phenols, polyphenols, esters of phenols, esters ofpolyphenols, nonflavonoid phenolics, isothiocyanates, vitamins andvitamin cofactors, such as vitamin A, vitamin C, vitamin E, vitamin Ephosphate and ubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10),ubiquinol, pyrroloquinoline quinone (PQQ), ascorbic acid, citric acid,rosemary oil, minerals, such as mineral selenium and manganese,melatonin, α-carotene, β-carotene, lycopene, lutein, zeanthin,crypoxanthin, resveratrol, eugenol, quercetin, catechin, gossypol,hesperetin, curcumin, turmeric, turmeric/curcumin blend, ferulic acid,thymol, hydroxytyrosol, thyme, olive oil, lipoic acid, includingalpha-lipoic acid, glutathione, oxalic acid, tocopherol,tocopherol-derived compounds, di-alpha-tocopheryl phosphate,tocotrienols, butylated hydroxyanisole, butylated hydroxytoluene,ethylenediaminetetraacetic acid, tert-butylhydroquinone, acetic acid,pectin, zeaxanthin, astaxanthin, canthaxanthin, saponins, limonoids,kaempferol, myricetin, isorhamnetin, proanthocyanidins, quercetin,rutin, luteolin, apigenin, tangeritin, naringenin, eriodictyol,flavan-3-ols (e.g., anthocyanadins), gallocatechins, epicatechin and itsgallate forms, epigallocatechin and its gallate forms, theaflavin andits gallate forms, thearubigins, isoflavone phytoestrogens, genistein,daidzein, glycitein, anythocyanins, delphinidin, malvidin, pelargonidin,peonidin, and hops (Humulus lupulus L.)-containing compounds. In oneexample, the antioxidant includes ubiquinol. In another example, theantioxidant includes alpha-lipoic acid. In another example, theantioxidant includes pyrroloquinoline quinone (PQQ). In yet anotherexample, the antioxidant includes a turmeric/curcumin composition.

Any non-polar ingredient that is an antioxidant or has antioxidantproperties can be included in the provided compositions. Exemplary of anantioxidant that can be used in the provided compositions isalpha-lipoic acid, for example, the alpha-lipoic acids sold by NutriChemResources Company (Walnut, Calif.) and Zhejiang Medicines & HealthProducts Import & Export Co., Ltd (Hangzhou, China), and any otheralpha-lipoic acid. Another exemplary antioxidant that can be used in theprovided compositions is pyrroloquinoline quinone (PQQ), such as PureQQ,sold by Nascent Health Science (Allentown, N.J.). Exemplary of anon-polar ingredient that contains antioxidants that can be included inthe provided compositions is a turmeric/curcumin composition, forexample, the turmeric/curcumin composition that is 95% curcumin, sold bySiddharth International, Mumbai, India.

c. Non-Polar Solvents

The pre-emulsion concentrates and liquid nanoemulsion concentratesprovided herein can further contain a non-polar solvent, for example, anoil. The non-polar solvent can be included in the composition inaddition to the non-polar ingredient and can be used to dissolve thenon-polar ingredient. For example, the solvent can be an oil that doesnot contain the non-polar ingredient. When a non-polar solvent isincluded in the concentrates, it typically is used to dissolve thenon-polar ingredient before mixing with the other ingredients, forexample, before mixing with the other oil phase ingredients. Forexample, use of a non-polar solvent can reduce the crystal size and/orincrease the clarity of the aqueous liquid dilution compositioncontaining the diluted concentrate. Exemplary of non-polar solvents thatcan be used in the provided concentrates are oils (in addition to thenon-polar ingredients that are or contain non-polar compounds) such asvitamin E oil, flaxseed oil, CLA, borage oil, rice bran oil, D-limonene,canola oil, corn oil, MCT oil and oat oil. Other oils also can be used.Exemplary of a non-polar solvent suitable for use in the concentratesprovided herein includes vitamin E oil, such as the vitamin E oil soldby ADM Natural Health and Nutrition under the name Novatol™ 5-67 VitaminE (D-alpha-tocopherol; product code 410217; Decatur, Ill.), whichcontains at least 67.2% tocopherol and approximately 32.8% soybean oil.Another exemplary oil includes a flaxseed oil solvent, such as theflaxseed oil from Sanmark LLC (Greensboro, N.C.; Sanmark Limited,Dalian, Liaoning Province, China), which contains not less than (NLT)50% C18:3 alpha-linolenic acid.

When present in the pre-emulsion concentrates provided herein, thenon-polar solvent typically represents less than or about 50%, by weight(w/w), of the pre-emulsion concentrate, for example, less than or about45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% or less, by weight (w/w), ofthe concentrate.

When present in the liquid nanoemulsion concentrates provided herein,the non-polar solvent typically represents less than or about 15%, byweight (w/w), of the pre-emulsion concentrate, for example, less than orabout 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%or less, by weight (w/w), of the concentrate.

d. Preservatives and Sterilizers

The concentrates, e.g., pre-emulsion concentrates or liquid nanoemulsionconcentrates, provided herein can further contain one or morepreservatives (or preservativers) and/or sterilizers. The preservativeor sterilizer can be included to improve the stability of theconcentrate and the compositions made by diluting the concentrate, overtime. Preservatives can be added to preserve the ingredients, forexample, in order to prevent oxidation of the ingredients, for example,the non-polar ingredients, for example, the omega-3 containingcompounds, for example, the DHA. Preservatives, particularly food andbeverage preservatives, are well known. Any known preservative can beused in the provided concentrates. Exemplary of the preservatives thatcan be used in the provided concentrates are oil soluble preservatives,for example, benzyl alcohol, benzyl benzoate, methyl paraben, propylparaben, and antioxidants, for example, vitamin E, vitamin A palmitateand beta carotene. Typically, a preservative is selected that is safefor human consumption, for example, in foods and beverages, for example,a GRAS certified and/or Kosher-certified preservative, for example,benzyl alcohol.

The preservative typically represents less than 1%, less than about 1%,1% or about 1%, by weight (w/w), of the pre-emulsion concentrate orliquid concentrate or between 0.1% or about 0.1% and 1% or about 1%, byweight (w/w), of the concentrate, for example, 0.1%, 0.2%, 0.3%, 0.4%,0.5%, 0.6%, 0.7%, 0.725%, 0.75%, 0.8%, 0.9%, 1%, about 0.1%, about 0.2%,about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%,about 0.9%, about 1%, by weight (w/w), of the concentrate.

e. Polar Solvents

The liquid nanoemulsion concentrates and the liquid dilutioncompositions (i.e., beverages), further include polar solvents. Polarsolvents are well known in the art. The polarity of a solvent generallyindicates which compounds are soluble in the solvent, and with whichother solvents/liquids the solvent is miscible. Generally speaking,polar compounds are more readily solubilized in water and other polarsolvents than are non-polar ingredients. Polar solvents are more likelyto be miscible with water and other polar solvents and liquids.

The polarity of a solvent can be assessed by measuring a number ofdifferent parameters according to well-known methods (see, e.g.,Przybytek, “High Purity Solvent Guide,” Burdick and JacksonLaboratories, Inc., 1980), such as by determining a property of thesolvent, such as the dielectric constant, the dipole moment or thepolarity index. For example, polar solvents generally have highdielectric constants, typically dielectric constants greater than at orabout 15 (see, e.g., Lowery et al., “Mechanism and Theory in OrganicChemistry,” Harper Collins Publishers, 3rd ed., 1987, p. 177), such asat or about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 85, 90 orgreater than 90. For example, the dielectric constant of water is at orabout 80.10 at 20° C. Polar solvents generally have high polarityindices, typically greater than at or about 3 (see, e.g., Snyder,“Classification of the solvent properties of common liquids” (1974) J.Chromatog. A 92:223-230), such as at or about 3, 4, 5, 6, 7, 8 or 9 orgreater than 9. Polar solvents generally have large dipole moments,typically greater than at or about 1.4 Debye, such as at or about 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 3.0, 3.5, 4or greater than 4 Debye (see, e.g., “CRC Handbook of Chemistry andPhysics,” Lide, ed., 82nd edition, CRC Press, 2001, p. 15(14)-15(18)).Other methods of assessing solvent polarity are known in the art,including, but not limited to, the Kosower Z scale (Kosower, “Anintroduction to physical organic chemistry,” Wiley, 1969, p. 293), thedonor number and donor acceptor scale (Gutmann, “Solvent effects on thereactivities of organometallic compounds” (1976) Coord. Chem. Rev.18:225-255), and the Hildebrand solubility parameters (see, e.g.,Giddings et al., “High pressure gas chromatography of nonvolatilespecies. Compressed gas is used to cause migration of intractablesolutes” (1968) Science 162:67-73).

Polar solvents include polar protic solvents and polar aprotic solvents.A polar protic solvent (e.g., water, methanol, ethanol) contains ahydrogen atom attached to an electronegative atom, such that thehydrogen has a proton-like character and/or the bond between thehydrogen and electronegative atom is polarized. Polar aprotic solvents,on the other hand (e.g., acetone, acetonitrile), generally do notcontain positively polarized hydrogen atoms.

The polar solvents in the provided compositions typically are polarprotic solvents, including, but not limited to, water; alcohols, such asdihydric alcohols which contain two hydroxyl groups (for example,glycols, e.g., propylene glycol, ethylene glycol, tetraethylene glycol,triethylene glycol, trimethylene glycol), trihydric alcohols whichcontain three hydroxyl groups (e.g., glycerin, butane-1,2,3-triol,pentane-1,3,5-triol, 2-amino-2-hydroxymethyl-propane-1,3-diol),monohydric alcohols (e.g., methanol, ethanol, propanol, isopropanol,n-butanol and t-butanol) and other alcohols; and acids, such as aceticacid and formic acid. Other polar solvents include, but are not limitedto, acetone, acetonitrile, butyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, tetrahydrofuran andhexamethylphosphoric triamide. Typically, the polar solvent is water, oris an alcohol that typically contains two or more hydroxyl groups, suchas a trihydric or dihydric alcohol, such as, but not limited to,glycerol and propylene glycol. The polar solvents further include lowmolecular weight polyethylene glycols (PEGs), such as PEGs having amolecular weight not more than at or about 600 kDa, such as between orabout between 200 kDa and 600 kDa, typically not more than at or about400 kDa, for example, not more than 200 kDa.

In one example, the polar solvent has a dielectric constant greater thanat or about 15, and typically between at or about 20 and at or about 80,such as at or about 80.1. In another example, the polar solvent has apolarity index between at or about 3 and at or about 9. In anotherexample, the dipole moment of the polar solvent is between 1.5 and 3,and typically between at or about 1.8 and 2.8, such as 1.85 (fordielectric constants of solvents, see, for example, Landolt-Bornstein,New Series IV/17, “Static Dielectric Constants of Pure Liquids andBinary Liquid Mixtures,” Springer, 2008; and “CRC Handbook of Chemistryand Physics,” Lide, ed., 82nd edition, CRC Press, 2001; for dipolemoment of solvents, see, for example, “CRC Handbook of Chemistry andPhysics,” Lide, ed., 82nd edition, CRC Press, 2001; and for polarityindices of solvents, see, for example, Snyder, “Classification of thesolvent properties of common liquids,” J. Chromatography A, 92:223-230,1974).

When present, such as in the liquid nanoemulsion concentrates, theamount of the polar solvent typically is present in a highconcentration, for example, the total amount of polar solvent as apercentage (%), by weight, of the liquid concentrate (wt %) can be,e.g., from at or about 45% to at or about 80%, such as 45% to 50%, 45%to 55%, 45% to 60%, 45% to 65%, 45% to 70%, 45% to 75%, 50% to 55%, 50%to 60%, 50% to 65%, 50% to 70%, 50% to 75%, 50% to 80%, 55% to 60%, 55%to 65%, 55% to 70%, 55% to 75%, 55% to 80%, 60% to 65%, 60% to 70%, 60%to 75%, 60% to 80%, 65% to 70%, 65% to 75%, 65% to 80%, 70% to 75%, 70%to 80% and 75% to 80%, by weight, of the liquid concentrate. Exemplaryconcentrations of the polar solvent in the liquid nanoemulsionconcentrate are at or about 50%, 52%, 55%, 58%, 60%, 62%, 65%, 68%, 70%,72% and 76% (w/w) of the concentrate.

In the provided methods for making the liquid nanoemulsion concentrates,the polar solvent is added to the water phase. In one example, the polarsolvent is water, e.g., purified water, such as water that is purifiedprior to adding it to the concentrate formula, for example, by charcoalfilter, ion exchange, reverse osmosis, UV sterilization and/or filteringusing a filter, for example, a 50-100 micron filter. Typically, when afilter is used, it is an end point of use filter, which filters thewater before it reaches the tank in the provided process. Alternatively,previously filtered water can be added to the concentrates.

f. Co-Surfactants (Emulsifiers)

The concentrates, e.g., pre-emulsion concentrates and liquidnanoemulsion concentrates, can further contain one or moreco-surfactants (emulsifiers). For example, a co-surfactant can beincluded to improve emulsification of the non-polar ingredient and/orthe stability of the composition, for example, by preventing or slowingoxidation of the non-polar ingredient. Exemplary of a co-surfactant thatcan be used in the provided concentrates is a phospholipid, for example,phosphatidylcholine. Other exemplary co-surfactants include non-ionicsurfactants, such as sugar-derived surfactants, including fatty acidesters of sugars and sugar derivatives, and PEG-derived surfactants,such as PEG derivatives of sterols, PEG derivatives of fat-solublevitamins and PEG-sorbitan fatty acid esters.

When present, such as in the liquid nanoemulsion concentrates, theamount of the co-surfactant typically is present in a concentration lessthan or less than about 10%, typically less than or less than about 5%,for example, the total amount of co-surfactant as a percentage (%), byweight, of the liquid concentrate (wt %) can be, e.g., less than or lessthan about 10%, such as less than or about 5%, 4.5%, 4%, 3.5%, 3.15%,3%, 2.5%, 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, 0.5%, 0.25%, 0.15% or less,by weight, of the liquid concentrate.

i. Phospholipids

Exemplary of the co-surfactants that can be used in the providedcompositions are phospholipids. Phospholipids are amphipathic lipid-likemolecules, typically containing a hydrophobic portion at one end of themolecule and a hydrophilic portion at the other end of the molecule. Anumber of phospholipids can be used as ingredients in the providedcompositions, for example, lecithin, including phosphatidylcholine (PC),phosphatidylethanolamine (PE), distearoylphosphatidylcholine (DSPC),phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid(PA), phosphatidylinositol (PI), sphingomyelin (SPM) or a combinationthereof. Typically, the phospholipid is phosphatidylcholine (PC), whichsometimes is referred to by the general name “lecithin.” Exemplary ofthe phospholipids that can be used as co-surfactants in the providedcompositions are the phospholipids sold by Lipoid, LLC (Newark, N.J.),for example, Purified Egg Lecithins, Purified Soybean Lecithins,Hydrogenated Egg and Soybean Lecithins, Egg Phospholipids, SoybeanPhospholipids, Hydrogenated Egg and Soybean Phospholipids, SyntheticPhospholipids, PEG-ylated Phospholipids and phospholipid blends.Exemplary of the phosphatidylcholine that can be used as a co-surfactantin the provided compositions is the phosphatidylcholine composition soldby Lipoid, LLC, under the name Lipoid 5100, which is derived from soyextract and contains greater than or greater than about 95%phosphatidylcholine.

ii. Sugar-Derived Surfactants

Exemplary sugar-derived surfactants include, but are not limited to,sugar fatty acid esters including fatty acid esters of sucrose, glucose,maltose and other sugars, esterified to fatty acids of varying lengths(e.g., containing a varying numbers of carbons). The fatty acidstypically have carbon chains between 8 and 28 carbons in length, andtypically between 8 and 20, or between 8 and 18 or between 12 and 18,such as, but not limited to, stearic acid (18 carbons), oleic acid (18carbons), palmitic acid (16 carbons), myristic acid (14 carbons) andlauric acid (12 carbons). Typically, the sugar ester surfactants aresucrose ester surfactants, typically sucrose fatty acid estersurfactants.

iii. PEG-Derived Surfactants

Exemplary PEG-derived surfactants include, but are not limited to, PEGderivatives of sterols, e.g., a cholesterol or a sitosterol (including,for example, any of the PEG derivatives disclosed in U.S. Pat. No.6,632,443); PEG derivatives of fat-soluble vitamins, for example, someforms of vitamin A (e.g., retinol) or vitamin D (e.g., vitamin D1-D5);and PEG-sorbitan fatty acid esters, such as polysorbates, includingpolyoxyethylene (20) sorbitan monooleate (also called polysorbate 80)and analogs (e.g., homologs) of polysorbate 80, such as, for example,polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate40 (polyoxyethylene (20) sorbitan monopalmitate) and polysorbate 60(polyoxyethylene (20) sorbitan monostearate); and stearic acidderivatives, including, for example, polyethylene glycol 400 distearate(PEG 400 DS), such as the PEG 400 DS sold by Stepan Lipid Nutrition(Maywood, N.J.).

iv. Sucrose Fatty Acid Ester Surfactants

Sucrose fatty acid ester (SFAE) surfactants contain one or more sucrosefatty acid esters, which are non-ionic surfactants that contain sucrosein the hydrophilic portions and fatty acids in the hydrophobic portions.The sucrose fatty acid esters can be made by well-known methods (see,for example, U.S. Pat. Nos. 3,480,616; 3,644,333; 3,714,144; 4,710,567;4,898,935; 4,996,309; 4,995,911; 5,011,922 and 5,017,697 andInternational Patent Pub. No. WO 2007/082149), typically in anesterification reaction as described in U.S. Pub. No. 2012-0016026.

Because sucrose contains eight hydroxy (OH) groups, the esterificationreaction can join the sucrose molecule to one fatty acid molecule, orcan join it to a plurality of fatty acid molecules, producing differentdegrees of esterification, e.g., mono-, di-, tri- and poly-(up to octa-)fatty acid esters, but primarily mono-, di- and/or tri-esters. Thedegree of esterification can depend on conditions of esterification. Theesterification reaction can be carried out with a single type of fattyacid, or a plurality of fatty acids, such as fatty acids with varyingcarbon chain lengths, branched and linear fatty acids, and/or saturatedor unsaturated fatty acids. The esterification reaction with a singlefatty acid can produce a single ester, and typically forms more than oneester, such as mono- di-, tri- and/or poly-esters, formed from onereaction. The relative amounts of mono- di-tri- and/or poly-esters candepend on reaction conditions.

The fatty acid in the sucrose fatty acid ester can be any fatty acid,and can contain between 4 and 28 carbon atoms, typically between 8 and28 carbon atoms, and typically between 8 and 25 carbon atoms, such asbetween 8 and 18 carbon atoms, such as 8, 9, 10, 11, 12, 13, 14, 15, 16,17 and 18 carbon atoms. The fatty acid can be synthetic or naturallyoccurring, and include linear and branched fatty acids. The fatty acidsinclude, but are not limited to, myristic acid, palmitic acid, stearicacid, oleic acid, caproic acid, capric (or decanoic) acid, lauric acid,caprylic acid and pelargonic (or nonanoic) acid.

Thus, the sucrose fatty acid ester surfactants include sucrosemonoesters, diesters, triesters and polyesters, and mixtures thereof,and typically contain sucrose monoesters. The sucrose fatty acid estersurfactants include single fatty acid esters and also includehomogeneous mixtures of sucrose esters, containing members withdifferent lengths of fatty acid carbon chain and/or members withdifferent degrees of esterification. For example, the sucrose fatty acidester surfactants include mixtures of monoesters, diesters, triesters,and/or polyesters. The sugar ester surfactants further include sucrosefatty acid ester analogs and homologs and mixtures thereof.

In general, sucrose fatty acid esters, including mixtures of sucrosefatty acid esters, can have varying HLB values, such as HLB valuesranging from at or about 1 to at or about 20. The HLB value of thesucrose fatty acid ester generally depends on the degree ofesterification (e.g., the average degree of esterification in a mixtureof different esters). Typically, the lower the degree of esterification(e.g., average degree), the higher the HLB value of the sucrose fattyacid ester or mixture thereof. Exemplary sucrose esters include sucrosedistearate (HLB=3), sucrose distearate/monostearate (HLB 12), sucrosedipalmitate (HLB=7.4), sucrose monostearate (HLB=15), sucrosemonopalmitate (HLB>10), sucrose monolaurate (HLB 15). Typically, thesucrose fatty acid ester surfactants in the provided concentrates havean HLB value of between at or about 13 and at or about 20, such as at orabout 13, 14, 15, 16, 17, 18, 19, or 20, and typically between at orabout 13 and at or about 18, such as, but not limited to, HLB values ofat or about 15, 16 and 17, such as, for example, sucrose estersurfactants including sucrose monopalmitate, sucrose monolaurate andsucrose monostearate.

The sugar ester surfactants include sucrose ester blends, for example,sucrose ester mixtures containing a specified amount (e.g., percent, byweight) of sucrose monoesters. Exemplary surfactants include sucroseester mixtures having at least at or about 50%, by weight (w/w),monoester, such as at least or about at least 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99 or 100%, by weight (w/w), sucrosemonoesters, and typically at least at or about 60%, by weight, or atleast at or about 70%, by weight (w/w), monoesters.

The sucrose fatty acid ester surfactants include sucrose fatty acidmonoesters, such as sucrose monocaprylate, sucrose monodecanoate,sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate,sucrose monostearate, sucrose monopelargonate, sucrose monoundecanoate,sucrose monotridecanoate, sucrose monopentadecanoate and sucrosemonoheptadecanoate. The sucrose fatty acid esters further includemixtures containing varying percentages of monoesters, diesters,triesters and polyesters, such as, but not limited to, a mixture havingat or about 72% monoesters, 23% diesters, 5% triesters and 0%polyesters; a mixture having at or about 61% monoesters, 30% diesters,7% triesters, and 2% polyesters; and a mixture having at or about 52%monoesters, 36% diesters, 10% triesters and 2% polyesters.

The sucrose fatty acid ester surfactants include sucrose fatty acidesters sold under the trade name DK Ester®, produced by Dai-Ichi KogyoSeiyaku Co., Ltd of Japan (which, in some examples, can be producedaccording to the methods described in U.S. Pat. Nos. 4,898,935;4,996,309; 4,995,911; 5,011,922 and 5,017,697), and distributed throughMontello Inc., Tulsa, Okla., such as the F-160 and F-140 grade esterssold under the trade name DK Ester®, and sucrose esters sold under thetrade name SURFHOPE® SE PHARMA, by Mitsubishi-Kagaku Foods Corporation,distributed by Mitsubishi Chemical Performance Polymers, Inc. Thesesucrose fatty acid esters are mixtures of esters with different degreesof esterification. The sucrose fatty acid esters further include Ryotosugar esters, which are food-grade esters sold by Mitsubishi-KagakuFoods Corporation, distributed by Mitsubishi Chemical PerformancePolymers, Inc. Other exemplary sucrose fatty acid ester surfactants aredescribed in Youan et al. (2003) AAPS PharmaSci 5(2): Article 22 (1-9)and in Okamoto et al. (2005) Biol. Pharm. Bull. 28(9):1689-1694.

g. Emulsion Stabilizers (Co-Emulsifiers)

The provided liquid concentrates can further contain one or moreemulsion stabilizers (co-emulsifiers), which can be used to stabilizethe liquid nanoemulsion concentrate and/or the aqueous compositionscontaining the diluted concentrates. For example, the emulsionstabilizer can increase the viscosity of the liquid concentrate. One ormore emulsion stabilizers can be added, for example, during formulationafter evaluation of an initial concentrate, particularly if the oil andwater phases of the initial concentrate (or the aqueous liquid dilutioncomposition resulting from dilution of the initial concentrate) appearto be separating. Addition of the emulsion stabilizer can preventseparation of the oil and water phases.

Exemplary of an emulsion stabilizer that can be used in the providedcompositions is a composition containing a blend of gums, for example,gums used as emulsifying agents, for example, a blend containing one ormore of xanthan gum, guar gum and sodium alginate. Exemplary of such anemulsion stabilizer includes the emulsion stabilizer sold under thebrand name SALADIZER®, available from TIC Gums, Inc. (Belcamp, Md.).Other gums can be included in the emulsion stabilizer, for example, gumacacia, ester gums and sugar beet pectin. Exemplary emulsion stabilizersinclude modified food starches. These include the modified gum acaciasold under the name Tic Pretested® Ticamulsion® A-2010 Powder, availablefrom TIC Gums, Inc. (Belcamp, Md.). Other exemplary emulsion stabilizerscontaining an ester gum are, for example, the emulsion stabilizer soldunder the name Tic Pretested® Ester Gum 8BG, available from TIC Gums,Inc. (Belcamp, Md.) or Ester Gum 8BG, available from Hercules/Pinova(Brunswick, Ga.). Others sold by Ingredion, Inc (Westchester, Ill.)under the trademarks CAPSUL®, FIRMTEX®, THERMFLO®, THERMTEX®, andTEXTRA® and others, can be included in the compositions provided herein.Other blends of similar gums can also be used as emulsion stabilizers.

The emulsion stabilizer can be added to the water phase, the oil phase,or both the water and the oil phase, during formation of the liquidconcentrates and compositions. In one example, the emulsion stabilizeris added to the water phase at a concentration, such that it representsless than 1% or about 1% w/w of the liquid concentrate. In anotherexample, the emulsion stabilizer is added for a final concentration ofgreater than 1%, such as at or about 1.5% w/w of the liquid concentrate.In one example, the emulsion stabilizer is added to the water phase fora final concentration of between 0.1% or about 0.1% and 1% or about 1%,for example, 0.1%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%,0.19%, 0.2%, 0.25%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%,0.37%, 0.38%, 0.39%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% w/w of theliquid concentrate. In one example, the emulsion stabilizer is added tothe oil phase such that it represents less than 0.1% or about 0.1%, forexample, between 0.01% or about 0.01% and 0.1% or about 0.1%, forexample, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.061%, 0.062%,0.063%, 0.0635%, 0.07%, 0.08%, 0.09% or 0.1%, by weight (w/w), of theconcentrate. In one example, the emulsion stabilizer is added to thewater phase and the oil phase, for example, at a concentration withinthe oil and water phase concentration ranges listed above. In one suchexample, the emulsion stabilizer represents less than 1%, for example,between 0.01% or about 0.01% and 1% or about 1% (w/w), emulsionstabilizer, for example, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%,0.061%, 0.062%, 0.063%, 0.0635%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%,0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.25%, 0.3%,0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%,0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%, by weight (w/w), of the liquidconcentrate. The emulsion stabilizer, such as Ticamulsion, can be addedin higher concentrations, including 5%, 10%, 15%, 18%, 20%, or 25%, byweight, or more.

h. Flavors

The liquid nanoemulsion concentrates and compositions provided hereincan further contain one or more flavors or flavoring agents, forexample, any compound that can add flavor to the concentrate and/or tothe aqueous liquid dilution composition containing the dilutedconcentrate, for example, the food or beverage product containing theconcentrate. Several flavors are well known. Any flavor can be added tothe concentrates, for example, any flavor sold by Mission Flavors(Foothill Ranch, Calif.). Exemplary of flavors that can be used arefruit flavors, such as guava, kiwi, peach, mango, papaya, pineapple,banana, strawberry, raspberry, blueberry, orange, grapefruit, tangerine,lemon, lime and lemon-lime; cola flavors, tea flavors, coffee flavors,chocolate flavors, dairy flavors, root beer and birch beer flavors,methyl salicylate (wintergreen oil, sweet birch oil), citrus oils andother flavors. Typically, the flavors are safe and/or desirable forhuman consumption, for example, GRAS or Kosher-certified flavors. Anexemplary flavoring agent that can be used in the concentrates andcompositions provided herein are lemon oil, for example lemon oil soldby Mission Flavors (Foothill Ranch, Calif.), and D-limonene, forexample, 99% GRAS certified D-Limonene, sold by Florida Chemical (WinterHaven, Fla.). The flavor can be added, using the provided methods, tothe nanoemulsion concentrates after combining the oil and water phases.Alternatively, flavor(s) can be added to the water and/or oil phasedirectly.

i. pH Adjusters

One or more pH adjusters can be added to the provided liquidnanoemulsion concentrates, typically to the emulsion that is formedafter combining the water and oil phases according to the providedmethods. In particular, the pH adjuster can be used in compositionscontaining water. Alternatively, the pH adjuster can be added, at anappropriate concentration to achieve a desired pH, to the oil phaseand/or the water phase. Typically, the pH adjuster is added to adjustthe pH of the concentrate to within a range of 2.0 or about 2.0 to 4.0or about 4.0. One or more of a plurality of pH adjusting agents can beused. Typically, the pH adjusting agent is safe for human consumption,for example, GRAS certified. The pH adjuster can be citric acid. Anexemplary pH adjuster suitable for use with the concentrates providedherein includes the citric acid sold by Mitsubishi Chemical (Dublin,Ohio). Another exemplary pH adjuster is phosphoric acid, such as FoodGrade 80% Phosphoric Acid, sold by Univar.

Typically, the concentration of pH adjuster added to the provided liquidconcentrates is less than 5% or about 5%, for example, less than orabout 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%,0.4%, 0.3%, 0.2%, 0.1% or less, by weight, of the liquid concentrate.

j. Soluble Fibers

The liquid nanoemulsion concentrates provided herein can contain solublefiber. Soluble fibers include any soluble dietary fiber that can bereadily fermented in the colon, typically a plant based dietary fiber,for example, a soluble fiber from legumes, vegetables, such as broccoliand carrots, root vegetables, such as potatoes, sweet potatoes andonions, oats, rye, chia, barley and fruits, such as prunes, plums,berries, bananas, apples and pears. Typically, soluble dietary fibercontains non-starch polysaccharides, such as arabinoxylans, cellulose,dextrans, inulin, beta-glucans, fructo-oligosaccharides,oligosaccharides and polysaccharides. Soluble fibers include, but arenot limited to, fructo-oligosaccharides, for example, inulins, forexample, inulins found in chicory, Jerusalem artichoke, dahlia, garlic,leeks and onions, fructans and water-soluble soybean fiber. Exemplary ofa soluble fiber is an inulin, for example, Oliggo-Fiber Instant Inulin(Fibruline® Instant) (supplied by Cosucra-Groupe Warcoing SA, Belgium,sold by Gillco Products, San Marcos, Calif.), containing chicory inulin.

k. Additional Ingredients

The compositions, e.g., liquid dilution compositions and compositionsfor direct consumption, such as the soft gels and powders and pre-sprayemulsions, provided herein additionally can contain further ingredients.For example, compositions provided herein can contain one or morestabilizers (i.e., stabilizing system). The beverage compositions canadditionally contain sweeteners. The compositions provided herein alsocan contain, for example, pH adjusters and/or antifoaming agents.

i. Additional Non-Polar Compounds

The compositions provided herein can contain one or more additionalnon-polar compounds. The compositions, for example, the compositions fordirect consumption, such as the soft gels and powders and pre-sprayemulsions, can contain a non-polar ingredient that is a non-polarcompound or can contain an additional non-polar compound or both.Suitable additional non-polar compounds include any compound that caninduce, promote or enhance one or more effects, such as upon delivery toa subject or upon administration to a sample, for example,sympathomimetic effects, stimulatory effects, vasoconstriction,decongestion (e.g., bronchial or nasal decongestion), increased energy,endurance, mood-enhancement, appetite suppression and/or weight loss.The additional non-polar compounds include, but are not limited to,alkaloids, e.g., caffeine, synephrine, and γ-aminobutyric acid (GABA)derivatives, e.g., 4-amino-3-phenylbutyric acid (i.e., phenibut), plantextracts, particularly those with medicinal and herbal effects, and anycombination thereof (such as those described above in sectionD.1.b.vii.). Typically, the additional non-polar compounds arefood-approved, i.e., edible or ingestible, non-polar compounds, forexample, non-polar compounds that are safe and/or approved for humanconsumption.

In general, the compositions provided herein contain at least onenon-polar ingredient, i.e., at least one non-polar ingredient containingnon-polar compound, or an additional non-polar ingredient. Typically,when included in a beverage composition, the total amount of additionalnon-polar compound included in the provided beverage composition is lessthan 30% or about 30%, typically less than 20% or about 20%, forexample, less than 30%, 25%, 20%, 15%, 10%, 5%, 4.5%, 4%, 3.5%, 3%,2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the beveragecomposition.

ii. Stabilizers

The compositions provided herein contain one or more stabilizers, or astabilizing system. Stabilizers include any compound used to stabilizethe non-polar ingredients in the beverage compositions. The stabilizeror stabilizing system can aid in retaining one or more desirableproperties of the compositions, for example the appearance, taste orodor. The compositions provided herein containing non-polar ingredientsand a stabilizer or stabilizing system can retain one or more desirableproperties of the beverage composition for a period of time afterformulation, such as at or about 1, 2, 3, 4, 5, 6, or 7 days, at orabout 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 36 weeks, at or about 1, 2, 3,4, 5, 6, 8, 12, 18, 24, or 36 months, or at or about 1, 2, 3, or 4years. The stabilizers include, but are not limited to, carbonates andbicarbonates, acids, antioxidants, and any combination thereof.Typically the stabilizers or stabilizing system are food-approved, i.e.,edible or ingestible, stabilizers, for example, stabilizers that aresafe and/or approved for human consumption.

In general, the beverage compositions contain more than one stabilizer.

Typically, the total amount of stabilizers included in the providedbeverage compositions is less than 20% or about 20%, typically less than10% or about 10%, for example, less than 20%, 15%, 10%, 5%, 4.5%, 4%,3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the beveragecomposition.

(a) Bicarbonates or Carbonates

Exemplary of a stabilizer used in the provided beverage compositions isa bicarbonate or carbonate, for example, any edible or food-approvedbicarbonate or carbonate. Examples of suitable bicarbonates andcarbonates include sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, magnesium carbonate,zinc carbonate, and any combination thereof. In some examples, thecarbonate or bicarbonate is a carbonated beverage, such as a soda,flavored soda, carbonated water or carbonated juice. Alternatively, thebeverage can be carbonated by the addition of carbon dioxide. Selectionof suitable bicarbonates and carbonates for use in the provided beveragecompositions is within the skill of the skilled artisan.

Typically, the amount of bicarbonate or carbonate used in the providedbeverage compositions is between or between about 0.01% and 7%, byweight, of the composition, for example, between at or about 0.01% andat or about 6%, between at or about 0.01% and at or about 5%, between ator about 0.01% and at or about 4%, between at or about 0.01% and at orabout 3%, between at or about 0.01% and at or about 2%, between at orabout 0.01% and at or about 1%, between at or about 0.1% and at or about7%, between at or about 0.1% and at or about 6%, between at or about0.1% and at or about 5%, between at or about 0.1% and at or about 4%,between at or about 0.1% and at or about 3%, between at or about 0.1%and at or about 2%, between at or about 0.1% and at or about 1%, betweenat or about 0.5% and at or about 7%, between at or about 0.5% and at orabout 6%, between at or about 0.5% and at or about 5%, between at orabout 0.5% and at or about 4%, between at or about 0.5% and at or about3%, between at or about 0.5% and at or about 2%, between at or about0.5% and at or about 1%, between at or about 1% and at or about 7%,between at or about 1% and at or about 6%, between at or about 1% and ator about 5%, between at or about 1% and at or about 4%, between at orabout 1% and at or about 3%, between at or about 1% and at or about 2%,between at or about 2% and at or about 7%, between at or about 2% and ator about 5%, between at or about 2% and at or about 4%, between at orabout 3% and at or about 7%, between at or about 3% and at or about 5%,between at or about 4% and at or about 7%, between at or about 6% and ator about 7%, between at or about 5% and at or about 7%, or between at orabout 5% and at or about 6%, by weight, of the beverage composition. Insome examples, the amount of bicarbonate or carbonate used in theprovided beverage compositions is less than 7% or about 7%, typicallyless than 5% or about 5%, for example at or about 0.01%, 0.02%, 0.03%,0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%,3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%,4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%, 5.2%, 5.3%,5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.2%, 6.5%, 6.7%, or 7%, byweight, of the beverage composition.

(b) Acids

In one example, the stabilizer used in the beverage compositionscontains one or more acids, for example, any compound added to thebeverage composition that can lower the pH of the composition. The acidcan be, for example, an edible, ingestible or food-approved acid.Exemplary of suitable acids for use in the provided beveragecompositions are citric acid, phosphoric acid, adipic acid, ascorbicacid, lactic acid, malic acid, fumaric acid, gluconic acid, succinicacid, tartaric acid, maleic acid, and any combination thereof. In oneexample, the acid is citric acid.

Typically, the amount of acid added to the provided beveragecompositions is between or between about 0.01% and 5%, by weight, of thecomposition, for example, between at or about 0.01% and at or about 4%,between at or about 0.01% and at or about 3%, between at or about 0.01%and at or about 2%, between at or about 0.01% and at or about 1%,between at or about 0.1% and at or about 5%, between at or about 0.1%and at or about 4%, between at or about 0.1% and at or about 3%, betweenat or about 0.1% and at or about 2%, between at or about 0.1% and at orabout 1%, between at or about 0.5% and at or about 5%, between at orabout 0.5% and at or about 4%, between at or about 0.5% and at or about3%, between at or about 0.5% and at or about 2%, between at or about0.5% and at or about 1%, between at or about 1% and at or about 5%,between at or about 1% and at or about 4%, between at or about 1% and ator about 3%, between at or about 1% and at or about 2%, between at orabout 2% and at or about 5%, between at or about 2% and at or about 4%,between at or about 2% and at or about 3%, between at or about 3% and ator about 5%, between at or about 3% and at or about 4%, or between at orabout 4% and at or about 5%, by weight, of the beverage composition. Insome examples, the amount of acid added to the provided beveragecompositions is less than 5% or about 5%, typically less than 4% orabout 4%, for example, at or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%,0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%,2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%,3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%,4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9% or 5%, by weight, of the beveragecomposition.

(c) Antioxidants

In one example, the stabilizer used in the beverage compositionscontains an antioxidant, for example, a molecule that is capable ofinhibiting the oxidation of other molecules. Antioxidants includemolecules that scavenge free radicals. Suitable antioxidants includethose that are used as ingredients in dietary supplements. Theantioxidant can be a natural antioxidant or a synthetic antioxidant.

Examples of antioxidants include, but are not limited to hormones,carotenoids, carotenoid terpenoids, non-carotenoid terpenoids,flavonoids, flavonoid polyphenolics (e.g., bioflavonoids), flavonols,flavones, phenols, polyphenols, esters of phenols, esters ofpolyphenols, nonflavonoid phenolics, isothiocyanates, vitamins andvitamin cofactors, such as vitamin A, vitamin C, vitamin E, vitamin Ephosphate and ubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10),ascorbic acid, citric acid, rosemary oil, minerals, such as mineralselenium and manganese, melatonin, α-carotene, β-carotene, lycopene,lutein, zeanthin, crypoxanthin, resveratrol, eugenol, quercetin,catechin, gossypol, hesperetin, curcumin, ferulic acid, thymol,hydroxytyrosol, tumeric, thyme, olive oil, lipoic acid, glutathione,glutamine, oxalic acid, tocopherol-derived compounds,di-alpha-tocopheryl phosphate, tocotrienols, butylated hydroxyanisole,butylated hydroxytoluene, ethylenediaminetetraacetic acid,tert-butylhydroquinone, acetic acid, pectin, tocotrienol, tocopherol,coenzyme Q10 (coQ10), zeaxanthin, astaxanthin, canthaxanthin, saponins,limonoids, kaempferol, myricetin, isorhamnetin, proanthocyanidins,quercetin, rutin, luteolin, apigenin, tangeritin, hesperetin,naringenin, eriodictyol, flavan-3-ols (e.g., anthocyanadins),gallocatechins, epicatechin and its gallate forms, epigallocatechin andits gallate forms theaflavin and its gallate forms, thearubigins,isoflavone phytoestrogens, genistein, daidzein, glycitein,anythocyanins, cyaniding, delphinidin, malvidin, pelargonidin andpeonidin. In one example, the antioxidant is vitamin C. In anotherexample, the antioxidant is a coenzyme Q-containing compound, such asubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10).

Typically, the amount of antioxidant added to the provided beveragecompositions is between at or about 0.01% and at or about 3%, forexample, between at or about 0.01% and at or about 2.5%, between at orabout 0.01% and at or about 2%, between at or about 0.01% and at orabout 1.5%, between at or about 0.01% and at or about 1%, between at orabout 0.01% and at or about 0.5%, between at or about 0.05% and at orabout 3%, between at or about 0.05% and at or about 2.5%, between at orabout 0.05% and at or about 2%, between at or about 0.05% and at orabout 1.5%, between at or about 0.05% and at or about 1%, between at orabout 0.05% and at or about 0.5%, between at or about 0.1% and at orabout 3%, between at or about 0.1% and at or about 2.5%, between at orabout 0.1% and at or about 2%, between at or about 0.1% and at or about1.5%, between at or about 0.1% and at or about 1%, between at or about0.1% and at or about 0.5%, between at or about 0.5% and at or about 3%,between at or about 0.5% and at or about 2.5%, between at or about 0.5%and at or about 2%, between at or about 0.5% and at or about 1.5%,between at or about 0.5% and at or about 1%, between at or about 1% andat or about 3%, between at or about 1% and at or about 2.5%, between ator about 1% and at or about 2%, between at or about 1% and at or about1.5%, between at or about 1.5% and at or about 3%, between at or about1.5% and at or about 2.5%, between at or about 1.5% and at or about 2%,between at or about 2% and at or about 3%, between at or about 2% and ator about 2.5%, between at or about 2.5% and at or about 3%, by weight,of the beverage composition. In some examples, the amount of antioxidantadded to the provided beverage compositions is less than 5% or about 5%,typically less than 3% or about 2%, for example, at or about 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%,0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%,1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%,2.7%, 2.8%, 2.9% or 3.0%, by weight, of the beverage composition.

2. Concentrates

a. Pre-Emulsion Concentrates

Exemplary of the provided compositions are pre-emulsion concentratescontaining one or more non-polar ingredients. The pre-emulsionconcentrates can be semi-solid compositions, typically having a waxy orcreamy consistency, for example, the consistency of a substance such aswax, for example, a lip balm, at room temperature, for example, at 25°C. or about 25° C., and become liquid at higher temperatures, forexample, when heated to higher temperatures, such as to 125° F. or about125° F., or to 50° C. or about 50° C. or to 60° C. or about 60° C.

The pre-emulsion concentrates can be diluted into aqueous media, usingthe provided methods, to form the provided liquid dilution compositionscontaining the water-soluble vitamin E derivative mixtures(compositions) and non-polar ingredients. The pre-emulsion concentratesare formulated such that dilution of the concentrates, for example, inaqueous media, yields a composition having one or more desirableproperties, for example, clarity; safety; taste; smell; stability, forexample, lack of phase separation, “ringing” and/or precipitation overtime; and/or bioavailability. In one example, the desirable property isthe ability of the provided pre-emulsion concentrates to yield a clearor partially clear aqueous liquid dilution composition when it isdiluted into aqueous medium, for example, a beverage such as water. Inanother example, the desirable property relates to the safety of thepre-emulsion concentrates and/or the desirability of the pre-emulsionconcentrates for human consumption, for example, in foods and beverages.In another example, it can be desirable that the pre-emulsionconcentrate contains less than or equal to a particular concentration ofone or more ingredients. In another example, it can be desirable thatthe pre-emulsion concentrate contains greater than or equal to aparticular concentration of one or more ingredients.

In addition to the non-polar ingredients, the pre-emulsion concentratescontain at least one surfactant, such as the water-soluble vitamin Ederivative mixtures (compositions) described herein. Typically, thesurfactant has an HLB value between 12 or about 12 and 20 or about 20,for example, 12, 13, 14, 15, 16, 17, 18, 19, or 20, about 12, about 13,about 14, about 15, about 16, about 17, about 18, about 19, or about 20.Exemplary of suitable surfactants are tocopherol polyethylene glycolsuccinate (TPGS), such as the TPGS, TPGS analogs, TPGS homologs and TPGSderivatives described herein, and other surfactants having similarproperties to TPGS, for example, other surfactants having HLB valuesbetween 12 or about 12 and 20 or about 20. Typically, the surfactant isa natural surfactant, for example, a surfactant that is GRAS (generallyrecognized as safe)-certified by the FDA and/or Kosher certified, forexample, TPGS.

Typically, the pre-emulsion concentrates further contain one or moreadditional ingredients. Exemplary of additional ingredients that can beincluded in the pre-emulsion compositions are preservatives, solvents,co-surfactants, emulsion-stabilizers, additional non-polar ingredients,and flavoring agents, as described herein.

Typically, the pre-emulsion concentrates are formulated such that, whendiluted into an aqueous medium (e.g., water), they yield a dilutioncomposition that is a nanoemulsion, in which the non-polar ingredient(s)are present in micelles. These micelles, containing the non-polaringredient surrounded by the one or more surfactants, facilitate thedispersion of the non-polar ingredient among the polar solvent(s) of theaqueous medium in the dilution compositions. Typically, the pre-emulsionconcentrates are formulated such that the micelles in the dilutioncomposition have a small or relatively small particle size, for example,less than 1000 or about 1000 nm, less than 500 or about 500 nm,typically less than 300 or about 300 nm, typically less than 250 orabout 250 nm, typically less than 200 or about 200 nm, for example, 0,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95, 100, 125, 150 or 200 nm. Smaller particle sizecorrelates with increased clarity of the dilution compositions thatresults from diluting the pre-emulsion concentrates. For example, aliquid with a smaller particle size can be more clear than a liquid witha larger particle size. Small particle size also can contribute to otherdesirable properties, for example, stability.

A number of parameters of the pre-emulsion concentrates, includingingredients, their relative concentrations, and methods for making thepre-emulsion concentrates, affect the particle size of the liquiddilution compositions made by diluting the pre-emulsion concentrates. Byextension, these parameters of the pre-emulsion concentrates also affectthe desirable properties of the dilution compositions, for example, theclarity of the dilution compositions. In particular, the nature of thesurfactant, particularly the HLB of the surfactant, and the relativeconcentrations of the surfactant and the non-polar ingredient in thepre-emulsion concentrates, contribute to small particle size and clarityof the dilution compositions. Typically, several of these parameters andproperties relate to one another. For example, several of the parameterscontribute to the particle size, typically small particle size. Particlesize contributes directly to clarity of the aqueous liquid dilutioncompositions containing the pre-emulsion concentrates. Particle sizealso can relate to other properties, for example, stability, lack of“ringing” and/or precipitate formation of the aqueous liquid dilutioncompositions containing the pre-emulsion concentrates.

Accordingly, properties of the ingredients and their relativeconcentrations in the pre-emulsion concentrates are important for theability of the pre-emulsion concentrate to yield desirable dilutioncompositions. Determining the appropriate ingredients, and relativeconcentrations thereof, that yield dilution compositions havingdesirable properties is carried out using the provided methods forformulating the pre-emulsion concentrates.

i. Formulating the Pre-Emulsion Concentrates

Using the provided formulation methods, the pre-emulsion concentratesare formulated by selecting ingredients and concentration ratios of theingredients that yield compositions having one or more desiredproperties. When formulating the pre-emulsion concentrates, selectedingredients and starting concentrations are used to make initialpre-emulsion concentrates, which typically are diluted, evaluated andmodified, if necessary.

As a first step in formulating the provided pre-emulsion concentrates,one or more initial pre-emulsion concentrates are made and evaluated fordesired properties. For this step, ingredients are selected, forexample, from one or more of the lists of ingredients provided below. Astarting concentration (weight percentage) of each selected ingredientis selected from within an appropriate concentration range for thatingredient or category of ingredient. For example, a starting surfactantconcentration, such as a water-soluble vitamin E derivative, e.g., TPGS,is selected from within an appropriate surfactant concentration range.In some cases, the initial pre-emulsion concentrate is formulated basedon the ingredients, and concentrations thereof, of an existingpre-emulsion concentrate having one or more desired properties.

The initial pre-emulsion concentrate(s) is then made, using the methodsfor making the pre-emulsion concentrates provided below, adding eachingredient at its starting concentration at the appropriate step. In oneexample, more than one initial pre-emulsion concentrate is made. Forexample, multiple initial pre-emulsion concentrates, each having adifferent concentration of one or more ingredients, can be made andcompared. For example, multiple initial pre-emulsion concentrates can bemade in order to test various representative concentrations within anappropriate concentration range for one or more particular ingredients.

In a typical example, the initial pre-emulsion concentrate is made byincluding at least one surfactant, such as the water-soluble vitamin Ederivative mixtures (compositions) described herein, having an HLB valuebetween 12 or about 12 and 20 or about 20, typically a tocopherylpolyethylene glycol succinate (TPGS) surfactant.

In one example, the starting concentration of the surfactant, forexample, a water-soluble vitamin E derivative mixture described herein,e.g., TPGS, is greater than 50% or about 50%, typically greater than 60%or about 60%, typically greater than 65% or about 65%, for example,greater than 70% or about 70%, for example, a starting concentrationwithin the concentration range of between 50% or about 50% and 95% orabout 95%, between 60% or about 60% and 95% or about 95%, typicallybetween 65% or about 65% and 90% or about 90%, for example, between 69%or about 69% and 90% or about 90%, for example, between 69% or about 69%and 89% or about 89%, for example, 65, 66, 67, 68, 69, 69.5, 69.9, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 79.5, 79.9, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 89.5, 89.9, or 90%, by weight, of the pre-emulsionconcentrate.

In another example, the starting concentration of the surfactant, forexample, a water-soluble vitamin E derivative mixture described herein,e.g., TPGS, is greater than 20% or about 20%, typically greater than 30%or about 30%, for example, between 30% or about 30% and 55% or about55%, for example, between 30% or about 30% and 50% or about 50%, forexample, between 30% or about 30% and 45% or about 45%, for example, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, or 55%, by weight, of the pre-emulsionconcentrate. This example is typically used for pre-emulsionconcentrates where the non-polar ingredient includes a phytosterol.

Also, in this typical example, the initial pre-emulsion concentratefurther includes at least one non-polar ingredient (e.g., non-polaringredient that is or contains a non-polar compound). In one example,the starting concentration of the non-polar ingredient (e.g., non-polaringredient that is or contains a non-polar compound), or the total ofall of the one or more non-polar ingredients, is chosen from within aconcentration range of between 5% or about 5% and 35% or about 35%,typically between 10% or about 10% and 30% or about 30%, for example,between 10% or about 10% and 20% or about 20%, or between 20% or about20% and 30% or about 30%, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%,by weight, of the pre-emulsion concentrate.

In another example, the starting concentration of the non-polaringredient (e.g., non-polar ingredient that is or contains a non-polarcompound), or the total of all of the one or more non-polar ingredients,is chosen from within a concentration range of between 1% or about 1%and 50% or about 50%. In this example, which typically is used whenusing more than one non-polar ingredient, the total concentration of thenon-polar ingredients is chosen from within a concentration range ofbetween 30% or about 30% and 55% or about 55%, for example between 40%or about 40% and 50% or about 50%, by weight, of the composition.Exemplary of starting concentrations for individual non-polaringredients used in this example are between 1% and 50%, for example,1%, 10.5%, 34%, or 45%, by weight, of the pre-emulsion concentrate, andother concentrations within the range.

In one example, the initial pre-emulsion concentrate further includesother ingredients, for example, preservative(s), for example, benzylalcohol; co-surfactant(s), for example, a phospholipid, e.g.,phosphatidylcholine; a non-polar solvent, for example, an oil, and/or anemulsion stabilizer. Typically, a polar solvent, e.g., water, is notadded as an ingredient to the pre-emulsion concentrate.

After making the initial pre-emulsion concentrate(s), the pre-emulsionconcentrate(s) is evaluated for one or more desired properties, forexample, the ability to form dilution compositions (e.g., clear dilutioncompositions or dilution compositions having a particular turbidityvalue, particle size or other property). The ability to form dilutioncompositions having one or more properties is assessed by diluting thepre-emulsion concentrate in aqueous medium, for example, diluting thepre-emulsion composition in the aqueous medium at a dilution factor ofbetween 1:10 or about 1:10 and 1:1000 or about 1:1000 or more, typicallybetween 1:10 or about 1:10 and 1:500 or about 1:500 or more, forexample, diluted not more than 1:10 or about 1:10, 1:20 or about 1:20,1:25 or about 1:25, 1:50 or about 1:50, 1:100 or about 1:100, 1:200 orabout 1:200, 1:250 or about 1:250, 1:300 or about 1:300, 1:400 or about1:400, 1:500 or about 1:500, for example, 1:10, 1:20, 1:25, 1:30, 1:35,1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90, 1:100, 1:110,1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:210,1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280, 1:290, 1:300,1:350, 1:400, 1:450, 1:500, or more. In one example, the dilution iscarried out by including one or more drops of the heated pre-emulsionconcentrate in the aqueous medium, for example, in 25 mL or more of theaqueous medium.

After evaluation, the ingredients, and/or concentrations thereof, can beadjusted in order to generate the desired properties in the finalpre-emulsion concentrate. Typically, the concentration of the non-polaringredient and/or the surfactant, for example, a water-soluble vitamin Ederivative composition, e.g., TPGS, is the concentration that isadjusted after evaluating the initial pre-emulsion concentrate.Similarly, when formulating multiple initial pre-emulsion concentrates,one or more of the non-polar ingredients and the surfactant are variedamong the multiple initial pre-emulsion concentrates. In some cases,following evaluation, it can be determined that additional ingredients(not included in the initial formulation) are needed or desirable forachieving the desired properties of a particular pre-emulsionconcentrate. This process can be repeated until a pre-emulsionconcentrate having the desired property or properties is generated.

ii. Exemplary Ingredients and Typical Concentration Ranges

Each of the provided pre-emulsion concentrates and other compositionscontains at least one non-polar ingredient, for example, a non-polaringredient that is or contains one or more non-polar compounds, and asurfactant, for example, the water-soluble vitamin E derivative mixtures(compositions) described herein, e.g., mixtures of monomers and dimersof TPGS. Any non-polar ingredient that is or contains one or morenon-polar compounds can be formulated with the provided methods andpre-emulsion concentrates. Several exemplary non-polar ingredients thatcan be incorporated into the provided concentrates are described hereinbelow. Typically, the non-polar ingredient is or contains a non-polarcompound, for example, an oil-based non-polar compound, for example, apolyunsaturated fatty acid (PUFA), a coenzyme Q, or a phytochemical.

In one example, for formulating the initial pre-emulsion concentrates,the starting concentration of the non-polar ingredient, or the total ofall the non-polar ingredients, typically is chosen from within aconcentration range of between 5% or about 5% and 35% or about 35%,typically between 10% or about 10% and 30% or about 30%, for example,between 10% or about 10% and 20% or about 20%, or between 20% or about20% and 30% or about 30%, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%,by weight, of the pre-emulsion concentrate. In another example, thestarting concentration of the non-polar ingredient (e.g., non-polaringredient that is or contains a non-polar compound), or the total ofall the non-polar ingredients, is chosen from within a concentrationrange of between 1% or about 1% and 50% or about 50%. In this example,which typically is used when using more than one non-polar ingredient,the total concentration of the non-polar ingredients is chosen fromwithin a concentration range of between 30% or about 30% and 55% orabout 55%, for example between 40% or about 40% and 50% or about 50%, byweight, of the concentrate. Exemplary of starting concentrations forindividual non-polar ingredients used in this example are between 1% and50%, for example, 1%, 10.5%, 34% or 45%, by weight, of the concentrate,and other concentrations within the range.

In addition to the non-polar ingredient, the pre-emulsion concentratescontain at least one surfactant that is the water-soluble vitamin Ederivative mixture described herein, such as TPGS. The surfactant has anHLB value of between 12 or about 12 and 20 or about 20, for example, 12,13, 14, 15, 16, 17, 18, 19 or 20. Exemplary of suitable surfactants arethe water-soluble vitamin E derivative mixtures (compositions) describedherein, such as TPGS, TPGS analogs, TPGS homologs and TPGS derivativesand other surfactants having similar properties, for example, anysurfactant having an HLB value between 12 or about 12 and 20 or about20, where vitamin E derivative is provided as a mixture of dimer andmonomer with at least 13% percent dimer, typically at least 29%, 35%, or50% dimer, and the remainder monomer and about or no more than 10%, 5%,4%, 3%, 2%, or 1% other minor contaminants, impurities or higher formsof polymer. Surfactants, HLB values and methods for determining HLBvalues are well known.

In one example, the starting concentration of water-soluble vitamin Ederivative mixtures (compositions) described herein, e.g., TPGS, isgreater than 50% or about 50%, typically greater than 60% or about 60%,typically greater than 65% or about 65%, for example, greater than 70%or about 70%, for example, a starting concentration within theconcentration range of between 50% or about 50% and 95% or about 95%,between 60% or about 60% and 95% or about 95%, typically between 65% orabout 65% and 90% or about 90%, for example, between 69% or about 69%and 90% or about 90%, for example, between 69% or about 69% and 89% orabout 89%, for example, 65, 66, 67, 68, 69, 69.5, 69.9, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 79.5, 79.9, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 89.5, 89.9, or 90%, by weight, of the pre-emulsion concentrate.

In another example, the starting concentration of the surfactant, forexample, the water-soluble vitamin E derivative mixtures (compositions)described herein, e.g., TPGS, is greater than 20% or about 20%,typically greater than 30% or about 30%, for example, between 30% orabout 30% and 55% or about 55%, for example, between 30% or about 30%and 50% or about 50%, for example, between 30% or about 30% and 45% orabout 45%, for example, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55%, by weight,of the pre-emulsion concentrate. This example is typically used forpre-emulsion concentrates where the non-polar ingredient includes aphytosterol.

One or more, typically more than one, additional ingredients can beadded to the initial pre-emulsion concentrate. For example, thepre-emulsion concentrates typically contain at least one preservative,typically a natural preservative, for example, benzyl alcohol. Exemplaryof other additional ingredients that can be added to the pre-emulsionconcentrates, including the initial pre-emulsion concentrates, areemulsion stabilizers, for example, a blend of gums; a non-polar solventfor the non-polar ingredient, for example, an oil other than thenon-polar ingredient, e.g., vitamin E oil or flax seed oil; a pHadjuster, for example, citric acid or phosphoric acid; one or moreflavoring agents, for example, D-limonene or lemon oil; a co-surfactant,for example, a phospholipid, e.g., phosphatidylcholine.

The appropriate concentration ranges for the additional ingredients aredescribed in individual sections below. Typically, the concentration ofthe additional ingredients depends, in part, on the concentrations ofthe non-polar ingredient and/or of the surfactant. Typically, theconcentrations of these three ingredients are the focus of theformulating methods. For example, when it is determined thatmodifications to ingredient concentrations in the initial pre-emulsionconcentrate should be made, it typically is the concentration of one ormore of these two ingredients, i.e., the non-polar ingredient and/orsurfactant, that is/are adjusted.

In one example, it can be desirable to add one or more of the additionalingredients after evaluation of the initial pre-emulsion concentrate,for example, in order to improve the pre-emulsion concentrate withrespect to one or more desired properties.

b. Liquid Nanoemulsion Concentrates

Provided herein are liquid nanoemulsion concentrates (also called“liquid concentrates”) containing the water-soluble vitamin E derivativemixtures described herein, one or more non-polar ingredients that are orcontain one or more non-polar compounds, and a polar solvent. The liquidconcentrates, which include emulsions, can be diluted into aqueousmedium to form aqueous liquid dilution compositions containing thewater-soluble vitamin E derivative mixtures described herein andnon-polar ingredients that are or contain non-polar compounds. Theliquid concentrates are formulated based on one or more desirableproperties, such as clarity; safety; taste; smell; stability, forexample, lack of phase separation, “ringing” and/or precipitation overtime; and/or bioavailability of the concentrate and/or the aqueousliquid dilution compositions containing the concentrate. In one example,the desirable property is the ability of the provided concentrate toyield a clear or partially clear aqueous liquid dilution compositionwhen it is diluted into aqueous medium, e.g., water, such as in abeverage product. In another example, the desirable property relates tothe safety of the concentrates and/or the desirability of the liquidconcentrates for human consumption, for example, in food and beverageproducts. In another example, it can be desirable that the liquidconcentrate contains less than or equal to a particular concentration ofone or more ingredients. In another example, it can be desirable thatthe liquid concentrate contains greater than or equal to a particularconcentration of one or more ingredients.

In addition to the water-soluble vitamin E derivative mixtures describedherein and non-polar ingredients, the liquid concentrates furthercontain a polar solvent, such as water (e.g., filtered water), or anyother edible aqueous liquid (e.g., propylene glycol or glycerin), orcombination thereof. Typically, the liquid concentrates contain a highamount of the polar solvent, for example, between or between about 50%and about 80%, by weight (w/w), of the liquid concentrate, typicallybetween or between about 50% and about 79%, by weight, of the liquidconcentrate.

Typically, the liquid concentrates further contain one or moreadditional ingredients. Exemplary of additional ingredients that can beincluded in the liquid concentrates are preservatives, non-polarsolvents, co-surfactants, emulsion stabilizers, pH adjusters, additionalnon-polar ingredients and flavoring agents.

The non-polar ingredients in the liquid concentrates and dilutioncompositions provided herein are contained in micelles. These micelles,containing the non-polar ingredients surrounded by the one or moresurfactants, allow dispersion of the non-polar ingredients among polarsolvents, for example, when the liquid concentrates are diluted to formaqueous liquid dilution compositions. The micelles containing thenon-polar ingredients typically have a small or relatively smallparticle size, for example, less than or less than about 1000 nm, lessthan or less than about 500 nm, less than or less than about 300 nm,less than or less than about 200 nm, for example, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100, 125, 150 or 200 nm. Smaller particle size correlates with clarityof the aqueous liquid dilution compositions containing the dilutedliquid concentrates. For example, a liquid with a smaller particle sizecan be more clear than a liquid with a larger particle size. Smallparticle size also can contribute to other desirable properties, forexample, stability.

A number of factors, including ingredients, their relativeconcentrations, and methods for making the liquid concentrates, affectthe particle size of the compositions, and other desirable properties ofthe compositions, such as clarity. In particular, the nature of thesurfactant, particularly the HLB of the surfactant, and the relativeconcentrations of polar solvent (e.g., water), surfactant and thenon-polar ingredient contribute to small particle size and clarity ofthe aqueous liquid dilution compositions. Typically, several of theseparameters and properties are related to one another. For example,several of the parameters contribute to the particle size, typicallysmall particle size, of the compositions. Particle size contributesdirectly to clarity of the aqueous liquid dilution compositionscontaining the liquid concentrates. Particle size also can relate toother properties, for example, stability, lack of “ringing” and/orprecipitate formation of the aqueous liquid dilution compositionscontaining the liquid concentrates.

Accordingly, properties of the ingredients and their relativeconcentrations in the liquid concentrates are important for the abilityof the concentrate to yield desirable dilution compositions. Providedare methods for formulating the liquid nanoemulsion concentrates.Determining the appropriate ingredients, and relative concentrationsthereof, that yield dilution compositions having desirable properties isperformed using provided methods for formulating the liquidconcentrates.

i. Formulating the Liquid Nanoemulsion Concentrates

In the provided formulation methods, the liquid concentrates areformulated by selecting ingredients and amounts of the ingredients thatyield compositions having one or more desired properties. Whenformulating the liquid concentrates, selected ingredients and startingamounts (concentrations) are used to make initial liquid concentrates,which are evaluated and modified, if necessary.

As a first step in formulating the provided liquid concentrates, one ormore initial concentrates are made and evaluated for desired properties.For this step, ingredients are selected, for example, from among theingredients described herein. The ingredients generally includesurfactants, for example, the water-soluble vitamin E derivativesdescribed herein, e.g., TPGS, polar solvents, non-polar ingredients, andother ingredients. A starting concentration (weight percentage) of eachselected ingredient is selected from within the appropriate range forthat ingredient or category of ingredient, for example, the appropriateconcentration range for the surfactant. In some cases, the initialliquid concentrate is formulated based on the ingredients and amounts(concentration) thereof of an existing liquid concentrate having one ormore desired properties.

The initial liquid concentrate is made, for example, using the methodsfor making the liquid concentrates, provided below, adding eachingredient at its starting concentration at the appropriate step. Morethan one initial liquid concentrate, e.g., multiple initial liquidconcentrates, each having a different concentration of one or moreingredients, can be made and compared. For example, multiple initialliquid concentrates can be produced to test various representativeconcentrations within an appropriate concentration range for one or moreparticular ingredients.

In a typical example, the initial liquid concentrate is made byincluding at least one surfactant, for example, a water-soluble vitaminE derivative described herein, e.g., TPGS, that has an HLB value ofbetween or about between 12 and 20, at a starting concentration withinthe concentration range of between or about between 5 wt % and 35 wt %of the liquid concentrate; at least one non-polar ingredient, at astarting concentration within the concentration range of between orabout between 1 wt % and 30 wt % of the liquid concentrate; and a polarsolvent, at a starting concentration of between or about between 40 wt %and 85 wt % of the liquid concentrate. In one example, the initialliquid concentrate further includes other ingredients, for example,preservatives, co-emulsifiers, pH adjusters and/or other ingredients asdescribed herein.

After making an initial liquid concentrate, the liquid concentrate canbe evaluated for one or more desired properties, for example, theability to form dilution compositions (e.g., clear dilution compositionsor dilution compositions having a particular turbidity value, particlesize or other property). The ability to form dilution compositionshaving one or more properties can be assessed by diluting the liquidconcentrate in an aqueous medium, such as water. For example, the liquidconcentrate can be diluted in an aqueous medium at a dilution factor ofbetween or about between 1:10 and 1:1000 or more, typically between orabout between 1:10 and 1:500 or more, for example, diluted not more than1:10 or about 1:10, 1:20 or about 1:20, 1:25 or about 1:25, 1:50 orabout 1:50, 1:100 or about 1:100, 1:200 or about 1:200, 1:250 or about1:250, 1:300 or about 1:300, 1:400 or about 1:400, 1:500 or about 1:500,for example, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, 1:55, 1:60, 1:65,1:70, 1:75, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160,1:170, 1:180, 1:190, 1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250,1:260, 1:270, 1:280, 1:290, 1:300, 1:350, 1:400, 1:450, 1:500 or more,or according to other dilutions provided herein.

After evaluation, the ingredients and/or amounts (concentrations)thereof can be adjusted in order to generate the desired properties inthe final liquid concentrate. Typically, the concentrations of thenon-polar ingredient, the surfactant, e.g., water-soluble vitamin Ederivative mixture, and/or the polar solvent are the concentrations thatare adjusted after evaluating the initial liquid concentrate. Similarly,when formulating multiple initial liquid concentrates, one or more ofthe non-polar ingredients, surfactant, e.g., water-soluble vitamin Ederivative, and polar solvent concentrations are varied among themultiple initial liquid concentrates. In some cases, followingevaluation, it can be determined that additional ingredients (notincluded in the initial formulation) are needed or desirable forachieving the desired properties of a particular concentrate. Thisprocess can be repeated until a liquid concentrate having the desiredproperty or properties is generated.

c. Liquid Dilution Compositions Containing the Concentrates

Among the products provided herein are liquid dilution compositions,typically aqueous liquid dilution compositions (i.e., beverages),containing the described concentrates containing the water-solublevitamin E derivative mixtures (compositions) described herein andnon-polar ingredients. The aqueous liquid dilution compositions are madeby diluting the provided liquid nanoemulsion concentrates into aqueousmedia, for example, beverages, for example, water, flavored water, soda,milk, juices, including fruit juices, sauces, syrups, soups, sportsdrinks, nutritional beverages, energy drinks, vitamin-fortifiedbeverages, or any beverage. Any beverage can be prepared or modifiedusing the water-soluble vitamin E derivative mixtures (compositions)described herein and other water-soluble vitamin E derivative mixtures(compositions), for example, see U.S. Pub. No. 2008-0254188 and U.S.Pat. No. 6,045,826.

In one example, the aqueous liquid dilution composition contains between0.05 grams (g) or about 0.05 g and 10 g or about 10 g, typically between0.05 g and 5 g, of the concentrate per 8 fluid ounces or about 8 fluidounces, at least 8 fluid ounces or at least about 8 fluid ounces, orless than 8 fluid ounces or less than about 8 fluid ounces, or perserving size, of the aqueous medium, for example, 0.05 g, 0.06 g, 0.07g, 0.08 g, 0.09 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8g, 0.9 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, or 10 g of theconcentrate per 8 fluid ounces, about 8 fluid ounces, or at least 8fluid ounces or at least about 8 fluid ounces of the aqueous medium, forexample 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,40, 45, 50, 100, 200 or more fluid ounces, of aqueous medium.

In another example, the aqueous liquid dilution composition containsbetween 1 mL or about 1 mL and 10 mL or about 10 mL of the concentrate,for example, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10mL of the concentrate, per 8 fluid ounces, about 8 fluid ounces, atleast 8 fluid ounces or at least about 8 fluid ounces, or less than 8fluid ounces or less than about 8 fluid ounces, or per serving size, ofthe aqueous medium, for example 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 25, 30, 35, 40, 45, 50, 100, 200 or more fluid ounces, ofaqueous medium.

In another example, the aqueous liquid dilution composition contains atleast 10 mg or about 10 mg, typically at least 25 mg or about 25 mg,typically at least 35 mg, of the non-polar ingredient, for example, anon-polar ingredient that is or contains the non-polar ingredient, per 8fluid ounces or about 8 fluid ounces, at least 8 fluid ounces or atleast about 8 fluid ounces of the aqueous medium, or less than 8 ouncesor less than about 8 ounces, or per serving size, of the aqueous medium;for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 325, 350, 375,400, 425, 450, 475, 500, 550, 600, 700, 800, 900, 1000, 1500, 2000 mg,or more, of the non-polar ingredient per at least 8 fluid ounces or atleast about 8 fluid ounces of aqueous medium. In another example, theaqueous liquid dilution composition contains the concentrate diluted ata dilution factor of between 1:10 or about 1:10 and 1:1000 or about1:1000 or more, typically between 1:10 or about 1:10 and 1:500 or about1:500 or more, for example, diluted not more than 1:10 or about 1:10,1:20 or about 1:20, 1:25 or about 1:25, 1:50 or about 1:50, 1:100 orabout 1:100, 1:200 or about 1:200, 1:250 or about 1:250, 1:300 or about1:300, 1:400 or about 1:400, 1:500 or about 1:500, for example, 1:10,1:20, 1:25, 1:30, 1:35, 1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80,1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180,1:190, 1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270,1:280, 1:290, 1:300, 1:350, 1:400, 1:450, or 1:500, or more. In anotherexample, the aqueous liquid dilution compositions contain the liquidconcentrate diluted to any amount. In another example, the dilution isless than 1:10 or about 1:10.

Properties of the provided concentrates that are diluted into theaqueous medium contribute to various properties of the providedresulting aqueous liquid dilution compositions, for example, clarity;desirability for human consumption, for example, pleasant taste, and/orsmell, for example, lack of “fishy” taste/smell, lack of “ringing” andlack of crystal formation; stability, for example, lack of oxidation,“ringing” and/or precipitation over time; and safety for humanconsumption. As described herein, the liquid concentrates are formulatedaccording to the desired properties of the aqueous liquid dilutioncompositions containing the concentrates.

d. Evaluation of the Concentrates and Liquid Dilution Compositions

The formulation methods can further include analysis of the initialconcentrates, e.g., the pre-emulsion concentrates and/or the liquidnanoemulsion concentrates, based on one or more desired properties, forexample, properties of an aqueous liquid dilution composition containingthe diluted concentrate such as clarity, color, smell, taste, safety,stability, “ringing” or forming of precipitates and/or the presence ofcrystals. For example, the methods typically include analyzing theability of the initial concentrate to form a clear liquid upon dilutionin an aqueous medium, such as by analysis of the clarity/turbidity ofthe resulting aqueous liquid dilution composition containing the initialconcentrate.

For evaluation of properties of the initial concentrates in an aqueousliquid dilution composition, the initial concentrates, e.g., thepre-emulsion concentrates and/or the liquid nanoemulsion concentrates,can be diluted into an aqueous medium, for example, water or anotherpolar solvent, at a dilution factor of between or about between 1:10 and1:1000, typically between or about between 1:10 and 1:500, for example,diluted at least or about 1:10, at least or about 1:20, at least orabout 1:25, at least or about 1:50, at least or about 1:100, at least orabout 1:200, at least or about 1:250, at least or about 1:300, at leastor about 1:400, or at least or about 1:500, for example, 1:10, 1:20,1:25, 1:30, 1:35, 1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90,1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190,1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280,1:290, 1:300, 1:350, 1:400, 1:450, or 1:500, or any other dilution, suchas others provided herein. Typically, clarity of the resulting aqueousliquid dilution composition containing the diluted initial concentrateis evaluated using one or more approaches. Additionally, otherproperties can be evaluated, for example, smell and/or taste propertiesof the liquid. For example, when the non-polar ingredient is apolyunsaturated fatty acid (PUFA), particularly fish oil or algae oil,the aqueous liquid dilution composition can be evaluated empirically fora “fishy” smell.

i. Clarity

Dilution of the provided concentrates, e.g., the pre-emulsionconcentrates and/or the liquid nanoemulsion concentrates, in aqueousmedia can yield clear liquids. The clarity of the resulting aqueousliquid dilution composition containing the initial concentrate can beevaluated by one or more of a plurality of approaches, such as byempirical observation, by measuring particle size and/or by measuringthe turbidity value of the liquid.

For example, the concentrates, e.g., the pre-emulsion concentratesand/or the liquid nanoemulsion concentrates, can be diluted to formclear liquids (or liquids that are equal in clarity to known liquids),by adding between or about between 0.05 grams (g) and 10 g of theconcentrate, such as between or about between 0.05 g and 5 g, forexample, about 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, 0.2 g, 0.3g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6g, 7 g, 8 g, 9 g, or 10 g of the concentrate, to aqueous medium, forexample, to at least or about at least 8 fluid ounces, such as at leastor about at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25,30, 35, 40, 45, 50, 100, or 200, or more fluid ounces of aqueous medium,e.g., water, to form a clear aqueous liquid dilution composition thatcontains the concentrate that contains the water-soluble vitamin Ederivative composition and non-polar ingredient. The concentrates can bediluted to form clear aqueous liquid dilution compositions by addingbetween or about between 1 mL and 10 mL of the concentrate, for example,about 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL or 10 mL ofthe concentrate to at least or about at least 8 fluid ounces of aqueousmedium, for example at least or about at least 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 100, or 200, or morefluid ounces of aqueous medium, e.g., water, to form a clear aqueousliquid dilution composition that contains the concentrate that containsthe water-soluble vitamin E derivative composition and non-polaringredient.

The provided concentrates, e.g., the pre-emulsion concentrates and/orthe liquid nanoemulsion concentrates, can be formulated using anynon-polar ingredient for dilution in an aqueous medium. The concentratecan be diluted in an aqueous medium, such as water, to form a clearaqueous liquid dilution composition at a dilution factor of between orabout between 1:10 and 1:1000, such as between or about between 1:10 and1:500, for example, when diluted not more than 1:10 or about 1:10, 1:20or about 1:20, 1:25 or about 1:25, 1:50 or about 1:50, 1:100 or about1:100, 1:200 or about 1:200, 1:250 or about 1:250, 1:300 or about 1:300,1:400 or about 1:400, 1:500 or about 1:500, for example, 1:10, 1:20,1:25, 1:30, 1:35, 1:40, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:90,1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190,1:200, 1:210, 1:220, 1:230, 1:235, 1:240, 1:250, 1:260, 1:270, 1:280,1:290, 1:300, 1:350, 1:400, 1:450, 1:500 or more. The clear liquid canbe formed at dilutions less dilute than 1:10 of the concentrate.Typically, the clarity of the liquid is maintained with increasingdilutions, for example, to infinity.

Clarity of the aqueous liquid dilution composition containing thediluted concentrate, e.g., the pre-emulsion concentrates and/or theliquid nanoemulsion concentrates, can be evaluated using one or more ofa plurality of approaches, for example, qualitatively, such as byempirical evaluation, or quantitatively, such as by measuring particlesize and/or by measuring the turbidity value of the liquid. In oneexample, the aqueous liquid dilution compositions are clear aqueousliquid dilution compositions or non-turbid aqueous liquid dilutioncompositions, for example, as determined, as described below,empirically or by measuring turbidity and/or particle size. In anotherexample, the aqueous liquid dilution compositions are not clear, or notcompletely clear. The liquid dilution compositions can be more or lessclear, or have the same clarity as another liquid, for example, anaqueous liquid dilution composition made according to the providedmethods or a beverage, for example, a beverage that does not contain thediluted concentrate.

For example, a particular quantitative or qualitative clarity value canbe desired. The emulsions and compositions provided herein, as well asthe aqueous liquid dilution compositions provided herein, are more clearthan the same compositions made with a corresponding lowdimer-containing water-soluble vitamin E derivative composition. Anaqueous liquid dilution composition containing the concentrate dilutedin a beverage product can be as clear or about as clear as the samebeverage containing no concentrate. The evaluation can be donequalitatively, for example by empirical observation, or quantitatively,for example, by calculating particle size and/or turbidity value (NTU)for the liquid(s).

Properties of the liquid concentrates can affect the clarity of theliquid. A number of parameters can vary the clarity of the liquids, forexample, the relative concentration of surfactant, non-polar ingredientand/or water; the type of non-polar ingredient; the concentration ofexcipient(s) in the particular non-polar ingredient; and the purity ofthe non-polar ingredient, for example, whether it has been standardizedto a high purity, or whether it is an extract or a filtered extract. Forexample, an aqueous liquid dilution composition made by diluting aconcentrate containing a non-polar ingredient that contains lecithin,for example a high amount of lecithin, can be less clear than one madewith a concentrate containing a non-polar ingredient that does notcontain lecithin. In another example, a liquid concentrate containing anon-polar ingredient that is a filtered extract can produce a cleareraqueous liquid dilution composition when diluted than a concentratecontaining a crude extract.

(a) Empirical Evaluation

The relative clarity/turbidity of the aqueous liquid dilutioncomposition containing the diluted concentrate, e.g., the pre-emulsionconcentrates and/or the liquid nanoemulsion concentrates, can beassessed qualitatively by observation. For example, a liquid can beconsidered clear if it does not have a cloudy appearance and/or if noparticles are visible when looking at the liquid with the naked eye.Clarity can be assessed empirically by comparison to other liquids, forexample, water, fruit juice, soda and/or milk. For example, it can bedesirable that the liquid is as clear or about as clear as water oranother liquid, for example a beverage. For example, the liquid(containing the concentrate diluted in an aqueous medium, for example, abeverage product) can be as clear or about as clear as the same aqueousmedium not containing the concentrate. In some cases, the aqueous liquiddilution composition is as clear or about as clear as water or anotherliquid, for example a beverage. In some examples, there is nosubstantial difference, for example, no observable difference, betweenthe aqueous liquid dilution composition containing the concentrate andthe same aqueous medium without the concentrate. A clear liquid is notnecessarily colorless, for example, a yellow liquid that contains novisible particles or cloudiness can be considered clear. In anotherexample, the liquid is clear or partially clear or substantially clearif no crystals are visible and/or if no “ringing” is observed on thecontainer containing the liquid.

(b) Particle Size or Number of Particles

Alternatively, the clarity of the aqueous liquid dilution compositioncontaining the diluted concentrate, e.g., the pre-emulsion concentratesand/or the liquid nanoemulsion concentrates, can be assessed bymeasuring the particle size and/or number of particles of the liquid.Methods for measuring particle size are known and any method formeasuring particle size that can measure particle sizes in theappropriate ranges as described below, can be used.

Particle size can be analyzed by commercial services, for example, fromDelta Analytical Instruments, Inc., such as by using a light-scatteringanalyzer, for example, a dynamic light scattering analyzer, e.g., theHoriba® LB-550, which can measure particle sizes within a range of 0.001microns to 6 microns and uses a Fourier-transform/iterativedeconvolution technique for reporting data and can measure sampleconcentrations from ppm to 40% solids; the Horiba® LA-920, which is alaser light-scattering instrument having an He—Ne laser and a tungstenlamp and can determine particle sizes from 0.02 microns to 2000 micronsusing Mie theory; or other analyzers known to those of skill in the art,for example, analyzers available from Delta Analytical Instruments, Inc.

Alternatively, the particle size can be measured microscopically, forexample, by viewing the liquid under a microscope, for example, at 640×magnification. With this method, particle size can be quantified bycomparing to a measuring device, for example, a ruler, which is visiblewhen viewing the liquid under the microscope. If any particles areobservable at this magnification, they are measured by comparison to themeasuring device. At a magnification of 640×, for example, any particlethat is about or greater than 25 nm is visible, while particle sizessmaller than 25 nm typically are not visible.

Typically, it is desired that the aqueous liquid dilution compositionshave a particle size less than or about less than 200 nm, for example,5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150,160, 170, 180, 190 or 200 nm. Typically, it is desired that the aqueousliquid dilution compositions have a particle size less than or aboutless than 100 nm, less than or about less than 50 nm, or less than orabout less than 25 nm. Typically, the particle size of the aqueousliquid dilution composition containing the concentrate is between orabout between 5 nm and 200 nm, or between 5 nm or about 5 nm and 50 nmor about 50 nm.

Typically, the particle size of the provided aqueous liquid dilutioncomposition containing the liquid concentrate, which contains thenon-polar ingredient, is smaller than the particle size of a liquidcontaining the non-polar ingredient (not formulated in a liquidconcentrate).

(c) Turbidity Measurement

Clarity of the liquid dilution composition can be analyzed by takingoptical turbidity measurements, which indicate the level of cloudinessor haziness of a liquid, correlating to the size and number of particlesin suspension in a liquid. For example, turbidity can be measuredoptically, to get a value indicating the cloudiness or haziness of theliquid, which correlates with particles in suspension in the liquid. Theunits of a turbidity value measured with a nephelometer are expressed asNephelometric Turbidity Units (NTU). The more clear a particular liquid,the lower its turbidity (i.e., NTU) value.

Turbidity can be measured optically, for example, using a nephelometer,an instrument with a light and a detector. The nephelometer measuresturbidity by detecting scattered light resulting from exposure of theliquid to an incident light. The amount of scattered light correlates tothe amount of particulate matter in the liquid. For example, a beam oflight passes through a sample with low turbidity with littledisturbance. Other methods for measuring turbidity are well known andcan be used with the provided methods and compositions.

The aqueous liquid dilution composition containing a dilutedconcentrate, e.g., the pre-emulsion concentrates and/or the liquidnanoemulsion concentrates, has low turbidity, for example, a turbidityvalue (NTU) less than or about 80, such as less than or about 70, lessthan or about 60, less than or about 50, less than or about 40, lessthan or about 30, less than or about 29, less than or about 28, lessthan or about 27, less than or about 26, less than or about 25, lessthan or about 24, less than or about 23, less than or about 22, lessthan or about 21, less than or about 20, less than or about 19, lessthan or about 18, less than or about 17, less than or about 16, lessthan or about 15, less than or about 14, less than or about 13, lessthan or about 12, less than or about 11, less than or about 10, lessthan or about 9, less than or about 8, less than or about 7, less thanor about 6, less than or about 5, less than or about 4, less than orabout 3, less than or about 2, less than or about 1, or about 0. Forexample, the turbidity value of the aqueous liquid dilution compositionsprovided herein typically is less than or about 80, for example, 80, 70,60, 50, 40, 30, 25, 20, 15, 10, 5, 4, 3, 2, 1 or less. The turbiditydepends upon the components of the compositions and amounts thereof. Inall instances, a composition provided herein that contains a highdimer-containing form of a water-soluble derivative of vitamin E, suchas a high dimer-containing TPGS composition, is less turbid than thesame composition that contains a low dimer-containing composition of thesame water-soluble derivative of vitamin E.

In one example, the clear aqueous liquid dilution composition has aturbidity value (NTU) less than or about 80, such as less than or about70, less than or about 60, less than or about 50, less than or about 40,less than or about 30, less than or about 29, less than or about 28,less than or about 27, less than or about 26, less than or about 25,less than or about 24, less than or about 23, less than or about 22,less than or about 21, less than or about 20, less than or about 19,less than or about 18, less than or about 17, less than or about 16,less than or about 15, less than or about 14, less than or about 13,less than or about 12, less than or about 11, less than or about 10,less than or about 9, less than or about 8, less than or about 7, lessthan or about 6, less than or about 5, less than or about 4, less thanor about 3, less than or about 2, less than or about 1, or about 0. Inanother example, the turbidity value of the aqueous liquid dilutioncomposition is less than or about 80, for example, 80, 70, 60, 50, 40,30, 25, 20, 15, or 10, or less.

ii. Stability

Typically, the provided aqueous liquid dilution compositions containingthe concentrates are stable, for example, free from one or more changesover a period of time, for example, 1 or more days, 1 or more weeks, 1or more months, or one or more years, for example, 1, 2, 3, 4, 5, 6, 7or more days, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12 or more months or 1, 2, 3, 4 or more years.

In one example, the liquid dilution compositions are stable because theyare free from oxidation or substantial oxidation over time. In anotherexample, they are stable because they remain clear over time. In anotherexample, the stable compositions remain safe and/or desirable for humanconsumption over time. In one example, stability refers to the lack ofprecipitates forming in the compositions over the period of time. In arelated example, the compositions are stable because they do not exhibit“ringing,” formation of a whitish or opaque ring around the perimeter ofthe container holding the liquid, typically at the surface of theliquid. Ringing typically is undesirable, particularly in the case of aliquid for human consumption, for example, a beverage.

In another example, the liquid dilution composition is stable if it doesnot exhibit any visible phase separation over a period of time, forexample, after 24 hours, after one week or after one month. In oneexample, the compositions are stable if they exhibit one or more ofthese described characteristics, over time, when kept at a particulartemperature. In one example, the liquid dilution compositions remainstable at room temperature, for example, 25° C. or about 25° C. Inanother example, the liquid dilution compositions remain stable atbetween 19° C. and 25° C. In another example, the liquid dilutioncompositions remain stable at refrigerated temperatures, for example, 4°C. or about 4° C., or at frozen temperatures, for example, at −20° C. orabout −20° C.

Stability refers to a desirable property of the provided liquid dilutioncompositions, for example, the ability of the provided liquid dilutioncompositions to remain free from one or more changes over a period oftime, for example, 1 or more days, 1 or more weeks, 1 or more months, orone or more years, for example, 1, 2, 3, 4, 5, 6, 7 or more days, 1, 2,3, 4, 5, 6, 7, 8, 9, 10 or more weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or more months or 1, 2, 3, 4 or more years. In one example, theliquid dilution composition is stable if it is formulated such that itremains free from oxidation or substantial oxidation over time. Inanother example, the stable liquid dilution compositions remain clearover time. In another example, the stable liquid dilution compositionsremain safe and/or desirable for human consumption over time. In oneexample, stability refers to the lack of precipitates forming in theliquid dilution compositions over the period of time. In a relatedexample, stability refers to the lack of “ringing” over the period oftime. In another example, the liquid dilution composition is stable ifit does not exhibit any visible phase separation over a period of time,for example, after 24 hours, after one week or after one month. In oneexample, the liquid dilution compositions are stable if they exhibit oneor more of these described characteristics, over time, when kept at aparticular temperature.

In one example, the liquid dilution compositions are stable at roomtemperature, for example, 25° C. or about 25° C. In another example, theliquid dilution compositions remain stable at between 19° C. and 25° C.In another example, the liquid dilution compositions remain stable atrefrigerated temperatures, for example, 4° C. or about 4° C., or atfrozen temperature, for example, at −20° C. or about −20° C.

iii. Advantageous Characteristics of Compositions for Human Consumption

A variety of properties of the concentrates and liquid dilutioncompositions can contribute to its desirability as a consumable product.For example, taste, smell, clarity, color, crystal formation,precipitation and “ringing,” are properties of interest. In one example,the liquid dilution composition has a pleasant taste and/or smell, forexample, due to one or more flavors added to the concentrate and/or tothe aqueous medium. In another example, the liquid dilution compositioncontaining the concentrate is free from an unpleasant taste or smell,for example, a “fishy” taste or smell. In one example, the liquiddilution composition smells or tastes less unpleasant, for example, lessfishy, compared to another aqueous liquid dilution composition. Inanother example, the aqueous liquid dilution composition does not havecrystals or has fewer crystals compared with another aqueous liquiddilution composition. In another example, the aqueous liquid dilutioncomposition is desirable because it does not exhibit ringing.

iv. Safety

Typically, the aqueous liquid dilution compositions containing theconcentrates are safe for human consumption, for example, containingonly ingredients approved by the FDA for human consumption, for exampleGRAS-certified ingredients. In one example, one or more of theingredients, for example, all the ingredients, are Kosher-certified.Safety of the liquid dilution compositions also relates to stabilityover time. Lack of or minimum oxidation of the liquid dilutioncompositions over time can contribute to the safety of the compositions.

v. Oral Bioavailability

In one example, the non-polar ingredients, for example, the non-polaringredients that are or contain non-polar compounds, contained in theaqueous liquid dilution compositions exhibit a high or relatively highbioavailability, for example, a bioavailability that is higher than aliquid containing the non-polar ingredient alone (i.e., not formulatedin the liquid concentrate). Bioavailability relates to the ability ofthe body to absorb the non-polar ingredient into a particular space,tissue cell and/or cellular compartment. Typically, non-polaringredients in liquids having small particle sizes are better absorbedthan those with larger particle sizes.

e. Selecting a Formulation and Modifying Formulations

After evaluating a concentrate, e.g., a pre-emulsion concentrate and/ora liquid nanoemulsion concentrate, or a liquid dilution composition,either a particular formula can be chosen or one or more modificationscan be made to the initial concentrate formula based on the results ofthe evaluation. When an initial concentrate does not display one or moredesired properties, e.g., to the desired extent, based on theevaluation, the concentration of one or more ingredients can be adjustedand another initial concentrate made. The process can be repeated untila concentrate with the desired properties is made. For modification ofthe initial concentrate, the amount of the polar solvent (in the liquidnanoemulsion concentrates), surfactant, e.g., water-soluble vitamin Ederivative, and/or non-polar ingredient can be adjusted, for example, byadjusting the concentration within the appropriate concentration range.Additional ingredients also can be chosen. For example, modification ofthe initial concentrates can involve the addition of one or moreadditional ingredients. For example, if evaluation reveals that the oiland water phases of the concentrate or aqueous liquid dilutioncomposition containing the diluted concentrate are separating, anemulsion stabilizer can be added to the formulation. In another example,a co-surfactant can be added to help emulsify the components of theconcentrate. In another example, the phase (oil phase or water phase),to which a particular ingredient is added, can be modified. For example,the formulation can be modified to change whether an ingredient is addedto the oil phase or the water phase.

When evaluation of the initial concentrate, e.g., the pre-emulsionconcentrates and/or the liquid nanoemulsion concentrates, reveals thatit has the desired properties, no modifications are made. In thisexample, the formula of the initial concentrate is used for making theconcentrate. When two or more initial concentrates are made, forexample, with increasing concentrations of an ingredient, the formula ofone of the initial concentrates can be chosen. Which formula is chosencan be based on which formula has the most desirable properties.Alternatively, desirable properties can be balanced with relativeamounts of ingredients. For example, a formulation that contains thelowest or the highest concentration of a particular ingredient, butstill provides a concentrate that yields a clear liquid upon dilution inan aqueous medium, for example, when formulating a liquid dilutioncomposition, can be selected.

Modifications can be effected even if the initial concentrate, e.g., thepre-emulsion concentrates and/or the liquid nanoemulsion concentrates,possesses the desired properties. For example, upon determining that aparticular concentrate formulation results in desired properties, theconcentration of one or more ingredients can be varied to determinewhether the same properties can be achieved if a higher or lowerconcentration of the ingredient is included. For example, the lowestconcentration of surfactant that can be used, while still generating aconcentrate with a desired property, for example, the ability to form aclear liquid upon dilution in an aqueous medium, can be determined. Inanother example, the highest concentration of the non-polar ingredientthat can be incorporated into a concentrate, while still maintaining thedesired property, for example, the ability of the concentrate to form aclear liquid upon dilution in an aqueous medium, can be determined. Inanother example, one or more additional ingredients can be added aftermaking an initial concentrate with desirable properties, for example,flavoring agents and/or pH adjusting agents.

3. Soft Gel and Pre-Gel Compositions Containing Non-Polar Ingredientsand the High Dimer-Containing PEG Derivative of Vitamin E Mixture

Methods and compositions for formulating compositions containingnon-polar ingredients are provided herein. Provided herein are soft gelcompositions containing a non-aqueous pre-gel concentrate in a shell orcoating that is suitable for human consumption, and methods forpreparing the compositions. The soft gel compositions containing anon-aqueous pre-gel concentrate contain one or more non-polaringredients, a surfactant, and a high amount (greater than 2%, 3%, 5%,6%, 7%, 10%, up to 20%) of non-aqueous solvent. The pre-gel compositionsalso are provided. By virtue of the ingredients, including the highamount of non-aqueous solvent, the pre-gel compositions exhibitadvantageous properties, such as, for example, the formulation of theingredients results in stable pre-gel concentrates that do not formprecipitates and exhibit enhanced bioavailability of the non-polaringredients, for example, when consumed.

In particular, the non-aqueous pre-gel concentrates provided hereincontain non-polar ingredients that are or contain non-polar compoundsand/or mixtures of non-polar compounds, at least one surfactant, and oneor more non-aqueous solvents. The pre-gel concentrates are encapsulatedby enclosing the pre-gel concentrates in a desired coating or shell toform the soft gel compositions provided herein. The pre-gel concentratescontain from 40% to as much as 90% of the non-polar ingredient, byweight, of the concentrate and between 5% and 20% non-aqueous solvent,and the remainder is/are surfactant(s), such as a PEG derivative ofvitamin E, particularly TPGS. The resulting compositions do not containprecipitated non-polar ingredients or compounds. The compositionsdescribed herein, in particular, the soft-gel compositions and pre-gelcompositions, contain high concentrations of non-polar ingredients andhave enhanced bioavailability, for example, after human consumption.Further description and examples of the pre-gel concentrates and softgel compositions are provided below.

For purposes herein, the pre-gel compositions include a non-aqueoussolvent that also can be a preservative. Exemplary of such solvents isbenzyl alcohol, in an amount that is significantly higher than theamount at which it is effective as an anti-microbial preservative.Hence, the compositions provided herein generally do not requireadditional preservatives.

a. Non-Aqueous Pre-Gel Compositions Containing Non-Polar Ingredients

Non-aqueous pre-gel compositions (also referred to as concentrates) thatcontain non-polar ingredients, a surfactant(s), and one or morenon-aqueous solvents are provided. The pre-gel concentrates areformulated by selecting ingredients and concentrations of theingredients as described herein that yield non-aqueous pre-gelconcentrates having one or more desired properties, for example, pre-gelconcentrates that do not contain any precipitated non-polar ingredientsor compounds. The pre-gel concentrates contain high concentrations ofthe non-polar ingredients ranging from at or about 30%-90% by weight ofthe pre-gel concentrate, from or about more than 5% to about or 20% byweight of the non-aqueous solvent, and a PEG derivative of vitamin E,such as TPGS, in an amount that is about or at 5% to 65%, by weight, ofthe pre-gel concentrate. Additional optional ingredients, such as othersurfactants, emulsifiers, and co-solvents, in amounts totaling less than5% or less than about 5% can be included.

By virtue of the high concentration of the non-polar ingredients, andalso the surfactant, the pre-gel concentrates as provided herein can bewaxy, having the consistency of a substance such as wax, for example, alip balm, or a semi-solid at room temperature, for example, at 25° C. orabout 25° C., and become liquid at higher temperatures, for example whenheated to higher temperatures, such as to 125° F. or about 125° F., orto 50° C. or about 50° C. or to 60° C. or about 60° C., or theconcentrates can be liquid. Whether the pre-gel concentrate is waxy(i.e., semi-solid) or a liquid depends upon the particular componentsand amounts thereof.

The pre-gel concentrates are then introduced into or formulated withmaterials, such as gelatins and/or gelatin replacements and otheringredients to form soft gel capsules. Each capsule is designed for oraladministration and typically contains an amount of the pre-gelcomposition sufficient to provide a single dosage or fractional amountof the non-polar ingredients or non-polar compounds.

i. Non-Polar Ingredients

The non-aqueous pre-gel concentrates provided herein contain one or morenon-polar ingredients that are or contain one or more non-polarcompounds. Non-polar ingredients include any lipophilic or lipid-solublecompound that has greater solubility in organic solvents (e.g., benzylalcohol, benzyl benzoate, d-limonene, ethanol, methanol, ethyl ether,acetone, and benzene) and in fats and oils, than in polar solvents, forexample, water. Typically, the non-polar ingredients are poorlywater-soluble, for example, water insoluble, or are compounds that havelow water solubility. The non-polar ingredients include, but are notlimited to, drugs, hormones, vitamins, nutrients and other lipophiliccompounds. Exemplary non-polar ingredients are listed herein below. Thenon-polar ingredient differs from the surfactant, e.g., polyalkyleneglycol derivative of vitamin E, for example, the non-polar ingredient isnot a polyalkylene glycol vitamin E derivative.

The non-polar ingredients are included in the pre-gel concentrate in anamount from about or at 30% to 90%, typically 35% to 85% or 40% to 90%,inclusive, or 45%-90%, 40%-85%, or 40%-75%, all inclusive by weight ofthe composition. The amount included depends upon the particularingredient and desired dosage.

The non-polar ingredients are any non-polar ingredients of interest, andinclude all described above (see, section D1, which is incorporatedhere) and elsewhere herein.

ii. Surfactants (High Dimer-Containing Water-Soluble Vitamin EDerivative Mixtures)

In addition to the one or more non-polar ingredients, each of theprovided pre-gel concentrates contains at least one surfactant selectedfrom among the high dimer-containing water-soluble vitamin E derivativesprovided and described herein. In particular, the pre-gel concentrationscontain a high dimer-containing PEG derivative of vitamin E composition,such as a higher dimer TPGS composition as described herein. The pre-gelconcentrates contain from about or at 5% to 50%, by weight, such asleast 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20% of the vitamin E derivative.

iii. Non-Aqueous Solvents

The pre-gel concentrates provided herein contain at least onenon-aqueous solvent, for example, any pharmaceutically acceptablesolvent that is non-aqueous that can dissolve the non-polar ingredientsprovided herein. The non-aqueous solvent, such as, but is not limitedto, benzyl alcohol, is included in the composition in a high amount,e.g., between 5% or about 5% and 20% or about 20%, such as, 5-15%,10%-15%, 5%-10%, at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, 20%, up to about or 20% or 25%. The non-aqueoussolvent dissolves the non-polar ingredients. The non-aqueous solvent isone that dissolves the non-polar ingredients and is different than ordoes not contain the non-polar ingredient. The non-aqueous solventprevents the non-polar ingredients from precipitating out of theconcentrate. The use of these higher amounts of non-aqueous solvent hasbeen found herein to provide advantageous properties, for example, inthe pre-gel concentrates and the soft gel compositions provided herein,when the soft gel compositions contain a pre-gel concentrate containingnon-polar ingredients and a surfactant along with high amounts ofnon-aqueous solvent. For example, the concentrates and soft gels do notcontain precipitated non-polar ingredients and provide enhancedbioavailability of the non-polar ingredients in the soft gelcompositions, for example, after consumption.

The one or more non-aqueous solvents included in the pre-gelconcentrates are typically insoluble or only partial soluble in water.For example, the non-aqueous solvents can include, but are not limitedto, alkanes, e.g., hydrocarbons and cyclic hydrocarbons, e.g.,d-limonene; aromatic compounds, such as aromatic alcohols, ethers andesters, e.g., benzyl alcohol and benzyl benzoate; haloalkanes, ethers,esters and ketones; organic solvents of natural origin, such as naturalhydrocarbons, for example, cyclic hydrocarbons, e.g., terpenes, forexample, d-limonene, alpha-pinene, beta-pinene, myrcene, linalol,citronellol, geraniol, menthol, citral, citronellal, or oxidized organicderivatives, in particular ethers, aldehydes, alcohols and esters;lactams, e.g., N-methyl pyrrolidone (NMP); alkylene glycols, e.g.,propylene glycol and polyethylene glycol (e.g., PEG300, PEG400);dimethyl sulfoxide; dimethyl acetamide; 2-pyrrolidone; C2-C6 alkanols;2-ethoxyethanol; alkyl esters such as 2-ethoxyethyl acetate, methylacetate, ethyl acetate, ethylene glycol diethyl ether, or ethyleneglycol dimethyl ether; (S)-(−)-ethyl lactate; acetone; glycerol; alkylketones such as methylethyl ketone or dimethyl sulfone; tetrahydrofuran;cyclic alkyl amides such as caprolactam; decylmethylsulfoxide; oleicacid; aromatic amines such as N,N-diethyl-m-toluamide;1-dodecylazacycloheptan-2-one; natural products, such as oils, includingolive oils and fatty acids, which can be saturated or non-saturated; andacyl glycerols. The pre-gel concentrates provided herein can contain onenon-aqueous solvent or more than one non-aqueous solvent, for example,two, three, or more non-aqueous solvents.

Typically, the non-aqueous solvent is an alcohol, an alcohol derivative,and/or a hydrocarbon that has little or no solubility in water.Exemplary of non-aqueous solvents that can be included in the pre-gelconcentrates are alcohols, for example, aromatic alcohols, e.g., benzylalcohol, such as the benzyl alcohol sold by Sigma Aldrich (St. Louis,Mo.); alcohol derivatives, for example, ester derivatives of alcohols,such as aromatic esters, e.g., benzyl benzoate; hydrocarbons, forexample, cyclic hydrocarbons, e.g., d-limonene, such as d-limonene thatis 99% GRAS-certified, sold by Florida Chemical, Winter Haven, Fla.; andany other non-aqueous solvent that is insoluble or has only partialsolubility in water.

iv. Co-Surfactants (Emulsifiers)

The concentrates, e.g., pre-emulsion concentrates and liquidnanoemulsion concentrates, can further contain one or moreco-surfactants (emulsifiers). For example, a co-surfactant can beincluded to improve emulsification of the non-polar ingredient and/orthe stability of the composition, for example, by preventing or slowingoxidation of the non-polar ingredient. Exemplary of a co-surfactant thatcan be used in the provided concentrates is a phospholipid, for example,phosphatidylcholine. Other exemplary co-surfactants include non-ionicsurfactants, such as sugar-derived surfactants, including fatty acidesters of sugars and sugar derivatives, and PEG-derived surfactants,such as PEG derivatives of sterols, PEG derivatives of fat-solublevitamins and PEG-sorbitan fatty acid esters.

When present, the amount of the co-surfactant typically is present in aconcentration less than or less than about 10%, typically less than orless than about 5%, for example, the total amount of co-surfactant as apercentage (%), by weight, of the liquid concentrate (wt %) can be,e.g., less than or less than about 10%, such as less than or about 5%,4.5%, 4%, 3.5%, 3.15%, 3%, 2.5%, 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%,0.5%, 0.25%, 0.15% or less, by weight, of the liquid concentrate.

(a) Phospholipids

Exemplary of the co-surfactants that can be used in the providedcompositions are phospholipids. Phospholipids are amphipathic lipid-likemolecules, typically containing a hydrophobic portion at one end of themolecule and a hydrophilic portion at the other end of the molecule. Anumber of phospholipids can be used as ingredients in the providedcompositions, for example, lecithin, including phosphatidylcholine (PC),phosphatidylethanolamine (PE), distearoylphosphatidylcholine (DSPC),phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid(PA), phosphatidylinositol (PI), sphingomyelin (SPM) or a combinationthereof. Typically, the phospholipid is phosphatidylcholine (PC), whichsometimes is referred to by the general name “lecithin.” Exemplary ofthe phospholipids that can be used as co-surfactants in the providedcompositions are the phospholipids sold by Lipoid, LLC (Newark, N.J.),for example, Purified Egg Lecithins, Purified Soybean Lecithins,Hydrogenated Egg and Soybean Lecithins, Egg Phospholipids, SoybeanPhospholipids, Hydrogenated Egg and Soybean Phospholipids, SyntheticPhospholipids, PEG-ylated Phospholipids and phospholipid blends.Exemplary of the phosphatidylcholine that can be used as a co-surfactantin the provided compositions is the phosphatidylcholine composition soldby Lipoid, LLC, under the name Lipoid S100, which is derived from soyextract and contains greater than or greater than about 95%phosphatidylcholine.

(b) Sugar-Derived Surfactants

Exemplary sugar-derived surfactants include, but are not limited to,sugar fatty acid esters including fatty acid esters of sucrose, glucose,maltose and other sugars, esterified to fatty acids of varying lengths(e.g., containing a varying numbers of carbons). The fatty acidstypically have carbon chains between 8 and 28 carbons in length, andtypically between 8 and 20, or between 8 and 18 or between 12 and 18,such as, but not limited to, stearic acid (18 carbons), oleic acid (18carbons), palmitic acid (16 carbons), myristic acid (14 carbons) andlauric acid (12 carbons). Typically, the sugar ester surfactants aresucrose ester surfactants, typically sucrose fatty acid estersurfactants.

(c) PEG-Derived Surfactants

Exemplary PEG-derived surfactants include, but are not limited to, PEGderivatives of sterols, e.g., a cholesterol or a sitosterol (including,for example, any of the PEG derivatives disclosed in U.S. Pat. No.6,632,443); PEG derivatives of fat-soluble vitamins, for example, someforms of vitamin A (e.g., retinol) or vitamin D (e.g., vitamin D1-D5);and PEG-sorbitan fatty acid esters, such as polysorbates, includingpolyoxyethylene (20) sorbitan monooleate (also called polysorbate 80)and analogs (e.g., homologs) of polysorbate 80, such as, for example,polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate40 (polyoxyethylene (20) sorbitan monopalmitate) and polysorbate 60(polyoxyethylene (20) sorbitan monostearate); and stearic acidderivatives, including, for example, polyethylene glycol 400 distearate(PEG 400 DS), such as the PEG 400 DS sold by Stepan Lipid Nutrition(Maywood, N.J.).

(d) Sucrose Fatty Acid Ester Surfactants

Sucrose fatty acid ester (SFAE) surfactants contain one or more sucrosefatty acid esters, which are non-ionic surfactants that contain sucrosein the hydrophilic portions and fatty acids in the hydrophobic portions.The sucrose fatty acid esters can be made by well-known methods (see,for example, U.S. Pat. Nos. 3,480,616; 3,644,333; 3,714,144; 4,710,567;4,898,935; 4,996,309; 4,995,911; 5,011,922 and 5,017,697 andInternational Patent Pub. No. WO 2007/082149), typically in anesterification reaction as described in U.S. Pub. No. 2012-0016026.

Because sucrose contains eight hydroxy (OH) groups, the esterificationreaction can join the sucrose molecule to one fatty acid molecule, orcan join it to a plurality of fatty acid molecules, producing differentdegrees of esterification, e.g., mono-, di-, tri- and poly-(up to octa-)fatty acid esters, but primarily mono-, di- and/or tri-esters. Thedegree of esterification can depend on conditions of esterification. Theesterification reaction can be carried out with a single type of fattyacid, or a plurality of fatty acids, such as fatty acids with varyingcarbon chain lengths, branched and linear fatty acids, and/or saturatedor unsaturated fatty acids. The esterification reaction with a singlefatty acid can produce a single ester, and typically forms more than oneester, such as mono- di-, tri- and/or poly-esters, formed from onereaction. The relative amounts of mono- di-tri- and/or poly-esters candepend on reaction conditions.

The fatty acid in the sucrose fatty acid ester can be any fatty acid,and can contain between 4 and 28 carbon atoms, typically between 8 and28 carbon atoms, and typically between 8 and 25 carbon atoms, such asbetween 8 and 18 carbon atoms, such as 8, 9, 10, 11, 12, 13, 14, 15, 16,17 and 18 carbon atoms. The fatty acid can be synthetic or naturallyoccurring, and include linear and branched fatty acids. The fatty acidsinclude, but are not limited to, myristic acid, palmitic acid, stearicacid, oleic acid, caproic acid, capric (or decanoic) acid, lauric acid,caprylic acid and pelargonic (or nonanoic) acid.

Thus, the sucrose fatty acid ester surfactants include sucrosemonoesters, diesters, triesters and polyesters, and mixtures thereof,and typically contain sucrose monoesters. The sucrose fatty acid estersurfactants include single fatty acid esters and also includehomogeneous mixtures of sucrose esters, containing members withdifferent lengths of fatty acid carbon chain and/or members withdifferent degrees of esterification. For example, the sucrose fatty acidester surfactants include mixtures of monoesters, diesters, triesters,and/or polyesters. The sugar ester surfactants further include sucrosefatty acid ester analogs and homologs and mixtures thereof.

In general, sucrose fatty acid esters, including mixtures of sucrosefatty acid esters, can have varying HLB values, such as HLB valuesranging from at or about 1 to at or about 20. The HLB value of thesucrose fatty acid ester generally depends on the degree ofesterification (e.g., the average degree of esterification in a mixtureof different esters). Typically, the lower the degree of esterification(e.g., average degree), the higher the HLB value of the sucrose fattyacid ester or mixture thereof. Exemplary sucrose esters include sucrosedistearate (HLB=3), sucrose distearate/monostearate (HLB 12), sucrosedipalmitate (HLB=7.4), sucrose monostearate (HLB=15), sucrosemonopalmitate (HLB>10), sucrose monolaurate (HLB 15). Typically, thesucrose fatty acid ester surfactants in the provided concentrates havean HLB value of between at or about 13 and at or about 20, such as at orabout 13, 14, 15, 16, 17, 18, 19, or 20, and typically between at orabout 13 and at or about 18, such as, but not limited to, HLB values ofat or about 15, 16 and 17, such as, for example, sucrose estersurfactants including sucrose monopalmitate, sucrose monolaurate andsucrose monostearate.

The sugar ester surfactants include sucrose ester blends, for example,sucrose ester mixtures containing a specified amount (e.g., percent, byweight) of sucrose monoesters. Exemplary surfactants include sucroseester mixtures having at least at or about 50%, by weight (w/w),monoester, such as at least or about at least 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99 or 100%, by weight (w/w), sucrosemonoesters, and typically at least at or about 60%, by weight, or atleast at or about 70%, by weight (w/w), monoesters.

The sucrose fatty acid ester surfactants include sucrose fatty acidmonoesters, such as sucrose monocaprylate, sucrose monodecanoate,sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate,sucrose monostearate, sucrose monopelargonate, sucrose monoundecanoate,sucrose monotridecanoate, sucrose monopentadecanoate and sucrosemonoheptadecanoate. The sucrose fatty acid esters further includemixtures containing varying percentages of monoesters, diesters,triesters and polyesters, such as, but not limited to, a mixture havingat or about 72% monoesters, 23% diesters, 5% triesters and 0%polyesters; a mixture having at or about 61% monoesters, 30% diesters,7% triesters, and 2% polyesters; and a mixture having at or about 52%monoesters, 36% diesters, 10% triesters and 2% polyesters.

The sucrose fatty acid ester surfactants include sucrose fatty acidesters sold under the trade name DK Ester®, produced by Dai-Ichi KogyoSeiyaku Co., Ltd of Japan (which, in some examples, can be producedaccording to the methods described in U.S. Pat. Nos. 4,898,935;4,996,309; 4,995,911; 5,011,922 and 5,017,697), and distributed throughMontello Inc., Tulsa, Okla., such as the F-160 and F-140 grade esterssold under the trade name DK Ester®, and sucrose esters sold under thetrade name SURFHOPE® SE PHARMA, by Mitsubishi-Kagaku Foods Corporation,distributed by Mitsubishi Chemical Performance Polymers, Inc. Thesesucrose fatty acid esters are mixtures of esters with different degreesof esterification. The sucrose fatty acid esters further include Ryotosugar esters, which are food-grade esters sold by Mitsubishi-KagakuFoods Corporation, distributed by Mitsubishi Chemical PerformancePolymers, Inc. Other exemplary sucrose fatty acid ester surfactants aredescribed in Youan et al. (2003) AAPS PharmaSci 5(2): Article 22 (1-9)and in Okamoto et al. (2005) Biol. Pharm. Bull. 28(9):1689-1694.

v. Emulsion Stabilizers (Co-Emulsifiers)

The compositions can further contain one or more emulsion stabilizers(co-emulsifiers), which can be used to stabilize the liquid nanoemulsionconcentrate and/or the aqueous compositions containing the dilutedconcentrates. For example, the emulsion stabilizer can increase theviscosity of the liquid concentrate. One or more emulsion stabilizerscan be added, for example, during formulation after evaluation of aninitial concentrate, particularly if the oil and water phases of theinitial concentrate (or the aqueous liquid dilution compositionresulting from dilution of the initial concentrate) appear to beseparating. Addition of the emulsion stabilizer can prevent separationof the oil and water phases.

Exemplary of an emulsion stabilizer that can included in the providedcompositions is a composition containing a blend of gums, for example,gums used as emulsifying agents, for example, a blend containing one ormore of xanthan gum, guar gum and sodium alginate. Exemplary of such anemulsion stabilizer includes the emulsion stabilizer sold under thebrand name SALADIZER®, available from TIC Gums, Inc. (Belcamp, Md.).Other gums can be included in the emulsion stabilizer, for example, gumacacia, ester gums and sugar beet pectin. Exemplary emulsion stabilizersinclude modified food starches. These include the modified gum acaciasold under the name Tic Pretested® Ticamulsion® A-2010 Powder, availablefrom TIC Gums, Inc. (Belcamp, Md.). Other exemplary emulsion stabilizerscontaining an ester gum are, for example, the emulsion stabilizer soldunder the name Tic Pretested® Ester Gum 8BG, available from TIC Gums,Inc. (Belcamp, Md.) or Ester Gum 8BG, available from Hercules/Pinova(Brunswick, Ga.). Others sold by Ingredion, Inc (Westchester, Ill.)under the trademarks CAPSUL®, FIRMTEX®, THERMFLO®, THERMTEX®, andTEXTRA® and others, can be included in the compositions provided herein.Other blends of similar gums can also be used as emulsion stabilizers.

In another example, the emulsion stabilizer is added for a finalconcentration of greater than 1%, such as at or about 1.5% w/w of theliquid concentrate. In one example, the emulsion stabilizer is added tothe water phase for a final concentration of between 0.1% or about 0.1%and 1% or about 1%, for example, 0.1%, 0.12%, 0.13%, 0.14%, 0.15%,0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.25%, 0.3%, 0.31%, 0.32%, 0.33%,0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,0.9% or 1% w/w of the composition. In one such example, the emulsionstabilizer represents less than 1%, for example, between 0.01% or about0.01% and 1% or about 1% (w/w), emulsion stabilizer, for example, 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.061%, 0.062%, 0.063%, 0.0635%,0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%,0.18%, 0.19%, 0.2%, 0.25%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%,0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%, byweight (w/w), of the liquid concentrate. The emulsion stabilizer, suchas Ticamulsion, can be added in higher concentrations, including 5%,10%, 15%, 18%, 20%, or 25%, by weight, or more.

vi. Flavors

The compositions provided herein can further contain one or more flavorsor flavoring agents, for example, any compound that can add flavor tothe concentrate and/or to the aqueous liquid dilution compositioncontaining the diluted concentrate, for example, the food or beverageproduct containing the concentrate. Several flavors are well known. Anyflavor can be added to the concentrates, for example, any flavor sold byMission Flavors (Foothill Ranch, Calif.). Exemplary of flavors that canbe used are fruit flavors, such as guava, kiwi, peach, mango, papaya,pineapple, banana, strawberry, raspberry, blueberry, orange, grapefruit,tangerine, lemon, lime and lemon-lime; cola flavors, tea flavors, coffeeflavors, chocolate flavors, dairy flavors, root beer and birch beerflavors, methyl salicylate (wintergreen oil, sweet birch oil), citrusoils and other flavors. Typically, the flavors are safe and/or desirablefor human consumption, for example, GRAS or Kosher-certified flavors. Anexemplary flavoring agent that can be used in the concentrates andcompositions provided herein are lemon oil, for example lemon oil soldby Mission Flavors (Foothill Ranch, Calif.), and D-limonene, forexample, 99% GRAS certified D-Limonene, sold by Florida Chemical (WinterHaven, Fla.). The flavor can be added, using the provided methods, tothe nanoemulsion concentrates after combining the oil and water phases.Alternatively, flavor(s) can be added to the water and/or oil phasedirectly.

vii. pH Adjusters

One or more pH adjusters can be added to the compositions at anappropriate concentration to achieve a desired pH. One or more of aplurality of pH adjusting agents can be used. The pH adjusting agent issafe for human consumption, for example, GRAS certified. The pH adjustercan be citric acid. An exemplary pH adjuster includes the citric acidsold by Mitsubishi Chemical (Dublin, Ohio). Another exemplary pHadjuster is phosphoric acid, such as Food Grade 80% Phosphoric Acid,sold by Univar.

viii. Soluble Fibers

The compositions provided herein can contain soluble fiber. Solublefibers include any soluble dietary fiber that can be readily fermentedin the colon, typically a plant based dietary fiber, for example, asoluble fiber from legumes, vegetables, such as broccoli and carrots,root vegetables, such as potatoes, sweet potatoes and onions, oats, rye,chia, barley and fruits, such as prunes, plums, berries, bananas, applesand pears. Typically, soluble dietary fiber contains non-starchpolysaccharides, such as arabinoxylans, cellulose, dextrans, inulin,beta-glucans, fructo-oligosaccharides, oligosaccharides andpolysaccharides. Soluble fibers include, but are not limited to,fructo-oligosaccharides, for example, inulins, for example, inulinsfound in chicory, Jerusalem artichoke, dahlia, garlic, leeks and onions,fructans and water-soluble soybean fiber. Exemplary of a soluble fiberis an inulin, for example, Oliggo-Fiber Instant Inulin (Fibruline®Instant; supplied by Cosucra-Groupe Warcoing SA, Belgium, sold by GillcoProducts, San Marcos, Calif.), containing chicory inulin.

ix. Stabilizers

The compositions provided herein contain one or more stabilizers, or astabilizing system. Stabilizers include any compound used to stabilizethe non-polar ingredients in the beverage compositions. The stabilizeror stabilizing system can aid in retaining one or more desirableproperties of the compositions, for example the appearance, taste orodor. The compositions provided herein containing non-polar ingredientsand a stabilizer or stabilizing system can retain one or more desirableproperties of the beverage composition for a period of time afterformulation, such as at or about 1, 2, 3, 4, 5, 6, or 7 days, at orabout 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 36 weeks, at or about 1, 2, 3,4, 5, 6, 8, 12, 18, 24, or 36 months, or at or about 1, 2, 3, or 4years. The stabilizers include, but are not limited to, carbonates andbicarbonates, acids, antioxidants, and any combination thereof.Typically the stabilizers or stabilizing system are food-approved, i.e.,edible or ingestible, stabilizers, for example, stabilizers that aresafe and/or approved for human consumption.

In general, the beverage compositions contain more than one stabilizer.Typically, the total amount of stabilizers included in the providedbeverage compositions is less than 20% or about 20%, typically less than10% or about 10%, for example, less than 20%, 15%, 10%, 5%, 4.5%, 4%,3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the beveragecomposition.

(a) Bicarbonates or Carbonates

Exemplary of a stabilizer used in the provided beverage compositions isa bicarbonate or carbonate, for example, any edible or food-approvedbicarbonate or carbonate. Examples of suitable bicarbonates andcarbonates include sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, magnesium carbonate,zinc carbonate, and any combination thereof. In some examples, thecarbonate or bicarbonate is a carbonated beverage, such as a soda,flavored soda, carbonated water or carbonated juice. Alternatively, thebeverage can be carbonated by the addition of carbon dioxide. Selectionof suitable bicarbonates and carbonates for use in the provided beveragecompositions is within the skill of the skilled artisan.

Typically, the amount of bicarbonate or carbonate used in the providedbeverage compositions is between or between about 0.01% and 7%, byweight, of the composition, for example, between at or about 0.01% andat or about 6%, between at or about 0.01% and at or about 5%, between ator about 0.01% and at or about 4%, between at or about 0.01% and at orabout 3%, between at or about 0.01% and at or about 2%, between at orabout 0.01% and at or about 1%, between at or about 0.1% and at or about7%, between at or about 0.1% and at or about 6%, between at or about0.1% and at or about 5%, between at or about 0.1% and at or about 4%,between at or about 0.1% and at or about 3%, between at or about 0.1%and at or about 2%, between at or about 0.1% and at or about 1%, betweenat or about 0.5% and at or about 7%, between at or about 0.5% and at orabout 6%, between at or about 0.5% and at or about 5%, between at orabout 0.5% and at or about 4%, between at or about 0.5% and at or about3%, between at or about 0.5% and at or about 2%, between at or about0.5% and at or about 1%, between at or about 1% and at or about 7%,between at or about 1% and at or about 6%, between at or about 1% and ator about 5%, between at or about 1% and at or about 4%, between at orabout 1% and at or about 3%, between at or about 1% and at or about 2%,between at or about 2% and at or about 7%, between at or about 2% and ator about 5%, between at or about 2% and at or about 4%, between at orabout 3% and at or about 7%, between at or about 3% and at or about 5%,between at or about 4% and at or about 7%, between at or about 6% and ator about 7%, between at or about 5% and at or about 7%, or between at orabout 5% and at or about 6%, by weight, of the beverage composition. Insome examples, the amount of bicarbonate or carbonate used in theprovided beverage compositions is less than 7% or about 7%, typicallyless than 5% or about 5%, for example at or about 0.01%, 0.02%, 0.03%,0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%,3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%,4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%, 5.2%, 5.3%,5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.2%, 6.5%, 6.7%, or 7%, byweight, of the beverage composition.

(b) Acids

In one example, the stabilizer included in the compositions contains oneor more acids, for example, any compound added to the beveragecomposition that can lower the pH of the composition. The acid can be,for example, an edible, ingestible or food-approved acid. Exemplary ofsuitable acids for use in the provided beverage compositions are citricacid, phosphoric acid, adipic acid, ascorbic acid, lactic acid, malicacid, fumaric acid, gluconic acid, succinic acid, tartaric acid, maleicacid, and any combination thereof. In one example, the acid is citricacid.

Typically, the amount of acid added to the provided beveragecompositions is between or between about 0.01% and 5%, by weight, of thecomposition, for example, between at or about 0.01% and at or about 4%,between at or about 0.01% and at or about 3%, between at or about 0.01%and at or about 2%, between at or about 0.01% and at or about 1%,between at or about 0.1% and at or about 5%, between at or about 0.1%and at or about 4%, between at or about 0.1% and at or about 3%, betweenat or about 0.1% and at or about 2%, between at or about 0.1% and at orabout 1%, between at or about 0.5% and at or about 5%, between at orabout 0.5% and at or about 4%, between at or about 0.5% and at or about3%, between at or about 0.5% and at or about 2%, between at or about0.5% and at or about 1%, between at or about 1% and at or about 5%,between at or about 1% and at or about 4%, between at or about 1% and ator about 3%, between at or about 1% and at or about 2%, between at orabout 2% and at or about 5%, between at or about 2% and at or about 4%,between at or about 2% and at or about 3%, between at or about 3% and ator about 5%, between at or about 3% and at or about 4%, or between at orabout 4% and at or about 5%, by weight, of the beverage composition. Insome examples, the amount of acid added to the provided beveragecompositions is less than 5% or about 5%, typically less than 4% orabout 4%, for example, at or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%,0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%,2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%,3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%,4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9% or 5%, by weight, of the beveragecomposition.

(c) Antioxidants

In one example, the stabilizer contains an antioxidant, for example, amolecule that is capable of inhibiting the oxidation of other molecules.Antioxidants include molecules that scavenge free radicals. Suitableantioxidants include those that are used as ingredients in dietarysupplements. The antioxidant can be a natural antioxidant or a syntheticantioxidant.

Examples of antioxidants include, but are not limited to hormones,carotenoids, carotenoid terpenoids, non-carotenoid terpenoids,flavonoids, flavonoid polyphenolics (e.g., bioflavonoids), flavonols,flavones, phenols, polyphenols, esters of phenols, esters ofpolyphenols, nonflavonoid phenolics, isothiocyanates, vitamins andvitamin cofactors, such as vitamin A, vitamin C, vitamin E, vitamin Ephosphate and ubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10),ascorbic acid, citric acid, rosemary oil, minerals, such as mineralselenium and manganese, melatonin, α-carotene, β-carotene, lycopene,lutein, zeanthin, crypoxanthin, resveratrol, eugenol, quercetin,catechin, gossypol, hesperetin, curcumin, ferulic acid, thymol,hydroxytyrosol, tumeric, thyme, olive oil, lipoic acid, glutathione,glutamine, oxalic acid, tocopherol-derived compounds,di-alpha-tocopheryl phosphate, tocotrienols, butylated hydroxyanisole,butylated hydroxytoluene, ethylenediaminetetraacetic acid,tert-butylhydroquinone, acetic acid, pectin, tocotrienol, tocopherol,coenzyme Q10 (coQ10), zeaxanthin, astaxanthin, canthaxanthin, saponins,limonoids, kaempferol, myricetin, isorhamnetin, proanthocyanidins,quercetin, rutin, luteolin, apigenin, tangeritin, hesperetin,naringenin, eriodictyol, flavan-3-ols (e.g., anthocyanadins),gallocatechins, epicatechin and its gallate forms, epigallocatechin andits gallate forms theaflavin and its gallate forms, thearubigins,isoflavone phytoestrogens, genistein, daidzein, glycitein,anythocyanins, cyaniding, delphinidin, malvidin, pelargonidin andpeonidin. In one example, the antioxidant is vitamin C. In anotherexample, the antioxidant is a coenzyme Q-containing compound, such asubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10).

Typically, the amount of antioxidant added to the compositions isbetween at or about 0.01% and at or about 3%, for example, between at orabout 0.01% and at or about 2.5%, between at or about 0.01% and at orabout 2%, between at or about 0.01% and at or about 1.5%, between at orabout 0.01% and at or about 1%, between at or about 0.01% and at orabout 0.5%, between at or about 0.05% and at or about 3%, between at orabout 0.05% and at or about 2.5%, between at or about 0.05% and at orabout 2%, between at or about 0.05% and at or about 1.5%, between at orabout 0.05% and at or about 1%, between at or about 0.05% and at orabout 0.5%, between at or about 0.1% and at or about 3%, between at orabout 0.1% and at or about 2.5%, between at or about 0.1% and at orabout 2%, between at or about 0.1% and at or about 1.5%, between at orabout 0.1% and at or about 1%, between at or about 0.1% and at or about0.5%, between at or about 0.5% and at or about 3%, between at or about0.5% and at or about 2.5%, between at or about 0.5% and at or about 2%,between at or about 0.5% and at or about 1.5%, between at or about 0.5%and at or about 1%, between at or about 1% and at or about 3%, betweenat or about 1% and at or about 2.5%, between at or about 1% and at orabout 2%, between at or about 1% and at or about 1.5%, between at orabout 1.5% and at or about 3%, between at or about 1.5% and at or about2.5%, between at or about 1.5% and at or about 2%, between at or about2% and at or about 3%, between at or about 2% and at or about 2.5%,between at or about 2.5% and at or about 3%, by weight, of the beveragecomposition. In some examples, the amount of antioxidant added to theprovided beverage compositions is less than 5% or about 5%, typicallyless than 3% or about 2%, for example, at or about 0.01%, 0.02%, 0.03%,0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%,

b. Formulating the Non-Aqueous Pre-Gel Concentrates Containing Non-PolarIngredients

The non-aqueous pre-gel concentrates contain one or more non-polaringredients; at least one surfactant, for example, a polyethylene glycolderivative of vitamin E, e.g., TPGS; and one or more non-aqueoussolvents, for example, solvents that have little or no solubility inwater, for example, an alcohol, ester, or hydrocarbon, or mixturesthereof.

As a first step in formulating the provided pre-gel concentrates, one ormore initial pre-gel concentrates are made and evaluated for desiredproperties. For this step, ingredients are selected, for example, fromone or more of the lists of ingredients provided below. A startingconcentration (weight percentage) of each selected ingredient isselected from within an appropriate concentration range for thatingredient or category of ingredient. For example, a starting surfactantconcentration, such as a polyethylene glycol derivate of vitamin E,e.g., TPGS, is selected from within an appropriate surfactantconcentration range. In some cases, the initial pre-gel concentrate isformulated based on the ingredients, and concentrations thereof, of anexisting pre-gel concentrate, having one or more desired properties.

The initial pre-gel concentrate(s) is then made, using the methods formaking described below, adding each ingredient at its startingconcentration at the appropriate step. In one example, more than oneinitial pre-gel concentrate is made. For example, multiple initialpre-gel concentrates, each having a different concentration of one ormore ingredients, can be made and compared. For example, multipleinitial pre-gel concentrates can be made in order to test variousrepresentative concentrations within an appropriate concentration rangefor one or more particular ingredient.

Each of the provided non-aqueous pre-gel concentrates contains at leastone non-polar ingredient, typically more than one non-polar ingredient,for example, non-polar ingredients that contain one or more non-polarcompounds. Any non-polar ingredient that contains one or more non-polarcompounds can be formulated with the provided methods and pre-gelconcentrates. Several exemplary non-polar ingredients that can beincorporated into the provided concentrates are described herein below.Typically, the non-polar ingredient is or contains a non-polar compound,for example, an oil-based ingredient, for example, a polyunsaturatedfatty acid (PUFA), a coenzyme Q, or a vitamin.

The non-aqueous pre-gel concentrates provided herein contain highamounts of non-polar ingredients, for example, between or between about30% or 35% or 40 wt % and 90 wt % non-polar ingredient, such as betweenor between about 40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%, 40%and 65%, 40% and 70%, 40% and 75%, 40% and 80%, 40% and 85%, 40% and90%, 45% and 50%, 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%,45% and 75%, 45% and 80%, 45% and 85%, 45% and 90%, 50% and 55%, 50% and60%, 50% and 65%, 50% and 70%, 50% and 75%, 50% and 80%, 50% and 85%,50% and 90%, 55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 55% and80%, 55% and 85%, 55% and 90%, 60% and 65%, 60% and 70%, 60% and 75%,60% and 80%, 60% and 85%, 60% and 90%, 65% and 70%, 65% and 75%, 65% and80%, 65% and 85%, 65% and 90%, 70% and 75%, 70% and 80%, 70% and 85%,70% and 90%, 75% and 80%, 75% and 85%, 75% and 90%, 80% and 85%, 80% and90%, and 85% and 90%, by weight of the pre-gel concentrate. The pre-gelconcentrates that contain high amounts of non-polar ingredients and highamounts of non-aqueous solvent exhibit desirable properties, forexample, the non-polar ingredients remain in solution in the non-aqueoussolvent and do not precipitate out.

In addition to the non-polar ingredients, the non-aqueous pre-gelconcentrates contain at least one surfactant, for example, apolyethylene glycol derivate of vitamin E. Typically, the surfactant hasan HLB value between 12 or about 12 and 20 or about 20, for example, 12,13, 14, 15, 16, 17, 18, 19, 20, about 12, about 13, about 14, about 15,about 16, about 17, about 18, about 19 or about 20. Exemplary ofsurfactants are those described above, including polyethylene glycolderivatives of vitamin E described herein, such as tocopherolpolyethylene glycol succinate (TPGS), such as the TPGS, TPGS analogs,TPGS homologs and TPGS derivatives described herein, and othersurfactants having similar properties to TPGS, for example, othersurfactants having HLB values between 12 or about 12 and 20 or about 20.Typically, the surfactant is a natural surfactant, for example, asurfactant that is GRAS (generally recognized as safe)-certified by theFDA and/or Kosher certified, for example, TPGS.

In the non-aqueous pre-gel concentrates provided herein, theconcentration of the surfactant, for example, the polyethylene glycolderivative of vitamin E, e.g., TPGS, is greater than 5% or about 5%,typically greater than 10% or about 10%, typically greater than 20% orabout 20%, for example, greater than 25% or about 25%, for example, aconcentration within the concentration range of between 5% or about 5%and 40% or about 40%, between 10% or about 10% and 40% or about 40%,typically between 20% or about 20% and 40% or about 40%, for example,between 25% or about 25% and 40% or about 40%, for example, at least,20, 21, 22, 23, 24, 25, 26, 27, 28, 28.25, 28.4, 29, 30, 31, 32, 33, 34,34.6, 35, 36, 37, 38, 39, or 40%, by weight, of the pre-gel concentrate.

The pre-gel concentrates contain one or more non-aqueous solvents, suchas solvents that are insoluble or only partial soluble in water.Typically, the non-aqueous solvent is an alcohol, a hydrocarbon, and/oran ester that has little or no solubility in water. Exemplary ofnon-aqueous solvents that can be included in the pre-gel concentratesare aromatic alcohols, including, but are not limited to, benzylalcohol, cyclic hydrocarbons, e.g., d-limonene, aromatic esters, e.g.,benzyl benzoate, and any non-aqueous solvent that is insoluble or hasonly partial solubility in water. Typically, an aqueous solvent, e.g.,water, is not added as an ingredient to the pre-gel concentrate. In thepre-gel concentrates provided herein, the concentration of thenon-aqueous solvent, or the total of all of the one or more non-aqueoussolvents, is chosen from within a concentration range of between 5% orabout 5% and 20% or about 20%, for example, at least 5, 6, 7, 7.5, 8, 9,10, 10.6, 11, 12, 13, 14, 15, 15.4, 16, 17, 18, 19, or 20%, by weight,of the pre-gel concentrate.

A number of parameters of the pre-gel concentrates, includingingredients, their relative concentrations, and methods for making thepre-gel concentrates, affect the desirable properties of theconcentrate, for example, the ability of the non-polar ingredients toremain in solution and not precipitate when a high concentration ofnon-polar ingredient is present. By extension, these parameters of thepre-gel concentrates also affect the desirable properties of the softgel compositions, for example, the bioavailability of the non-polaringredients in the soft gel composition after consumption, for example,human consumption. In particular, the nature of the surfactant,particularly the HLB of the surfactant, and the non-aqueous solvent, andthe relative concentrations of the surfactant, non-aqueous solvent, andnon-polar ingredients in the pre-gel concentrates, contribute to thedesirable properties of the pre-gel concentrates and thus, the soft gelcompositions.

Accordingly, properties of the ingredients and their relativeconcentrations in the pre-gel concentrates are important for the abilityof the pre-gel concentrates to yield desirable soft gel compositions.Selecting the appropriate ingredients and relative concentrationsthereof, within the ranges described herein, produce pre-gelconcentrates that can be introduced into gel capsules to yield soft gelcompositions having desirable properties.

c. Soft Gel Compositions Containing Non-Polar Ingredients

i. Capsules

The pre-gel concentrates are introduced into soft gel capsules toproduce the soft gels provided. The soft gel compositions contain anon-aqueous pre-gel concentrate within a shell or coating, typically, agel or similar capsule. The non-aqueous pre-gel concentrates describedherein that contain non-polar ingredients, a surfactant, and non-aqueoussolvent, are encapsulated in a coating or shell, such as a gel coating,to form the soft gel compositions provided herein. The resulting softgel compositions provided herein display advantageous properties, suchas enhanced bioavailability of the non-polar ingredients, for example,after the soft gel has been consumed. Methods for encapsulatingnon-aqueous pre-gel compositions are well known, and includeencapsulation into gelatin shells, or into shells composed ofalternative materials or combinations of materials are known to those ofskill in the art. Numerous vendors and companies provide such servicesand compositions. The soft gels containing the non-aqueous pre-gelconcentrates containing the non-polar ingredients provide a morebioavailable product compared to tablets or powders. When consumed, thesoft gel coating dissolves, releasing the contents.

Materials for encapsulation are well known. Capsules generally include ahigh proportion of gelatin (or a gelatin substitute) and additionalingredients, for example a plasticizer, to make the gel soft andpliable. Examples of the capsular materials include, but are not limitedto, natural or synthetic gelatin, pectin, casein, collagen, protein,modified starch, polyvinyl pyrrolidone, acrylic, natural or syntheticpolymers, cellulose derivatives (such as, but not limited to,hydroxypropyl methylcellulose (HPMC)), and combinations thereof,optionally with one or more plasticizers and/or water. In some examples,soft gel capsules are made to accommodate vegetarian or veganlifestyles. For such applications, alternative animal-free capsules,such as capsules made from seaweed extract and gluten free starchwithout modified sugars, can be used. Capsular materials also optionallyinclude one or more preservatives, coloring and opacifying agents suchas titanium dioxide to decrease the clarity of the shell of the soft gelcapsule, flavorings and sweeteners, sugars, gastroresistant substances,fillers, binders, lubricants, disintegrates, or combinations thereof. Insome embodiments, additional coatings on the capsules, such as immediaterelease coatings, protective coatings, enteric or delayed releasecoatings, sustained release coatings, barrier coatings, and combinationsthereof can be placed upon the soft gel coating. Flavors and up to 5%sucrose are added in certain examples in order to increase palatabilityof the soft gel prior to ingestion. In another example, in cases ofdecreased bioavailability of the non-aqueous pre-gel concentratescontaining non-polar ingredients, additional coatings can be added tothe soft gel that increase delivery of the non-polar ingredients.

Methods of manufacturing soft capsules are well known to the skilledartisan. Exemplary processes for manufacture of soft capsules include,but are not limited to, the plate process, the rotary die process, thereciprocating die process, the bubble process, and the continuousprocess (Ebert (1978), “Soft Elastic Gelatin Capsules: A Unique DosageForm,” Pharm. Tech. 1(5); Reich (2004), “Chapter 11: Formulation andphysical properties of soft capsules,” Pharmaceutical Capsules, 2d Ed.,Pharmaceutical Press, 201-212; Gullapalli, R. P. (2010) “Soft GelatinCapsules (Softgels),” J. Pharm. Sci. 99(10):4107-4146). Soft gelcapsules can be made using standard rotary die encapsulation technology,detailed in Stanley's Chapter 13 of “The Theory and Practice ofIndustrial Chemistry” (Lachman, Lieberman, and Kanig, Copyright Lea &Febiger, 1970) and in U.S. Patent Publication No. 2012/0301546 and U.S.Pat. Nos. 6,769,226 and 7,213,511). Capsules can be manufactured andthen hermetically sealed to form a one-piece hermetically sealed gelatinshell encasing the concentrate containing the non-polar ingredients.Capsules also can be manufactured according to methods to createseamless capsules (see, e.g., U.S. Pat. Nos. 5,478,508, 5,882,680 and4,780,316).

The capsules, for example, a gelatin capsule, can be manufactured inaccord with conventional methods, for example, as a two-piece hardgelatin capsule, sealed or unsealed, typically in standard shape andvarious standard sizes or as a soft gelatin capsule that is a one-piecehermetically sealed gelatin shell. The shape and size of the capsulescan vary in accordance with the method of preparation and the planneduse of the capsule. Capsule shapes can be tailored to the requirementsof specific products, including, but not limited to, tube-shaped topicaldisposable capsules, aplicaps for ophthalmic preparations,suppositories, or an oral dosage form. Additional capsule shapesinclude, but are not limited to, round, oval, tubular, oblong, twistoff, or a non-standard shape (e.g., a fish, tree, star, heart, or bear),and are preferably oblong. In some embodiments, non-standard shapes canbe used. The size of the capsule used will vary in accordance with thevolume of the fill composition, for example the volume of a pre-gelconcentrate containing non-polar ingredients, such as the non-aqueouspre-gel concentrates containing non-polar ingredients described herein,that are intended to be contained therein.

The soft gel capsules are filled with non-aqueous pre-gel concentratesprovided herein. Compositions for encapsulation by soft gel, such ascompositions containing non-polar ingredients, can be formulated in anyconventional manner by adding a selected amount of the concentrate, intoan acceptable soft gel capsule, such as a soft gelatin capsule.

Soft gel capsule fill volume typically depends upon the density of theencapsulated material, the particular ingredients and dosages desired ofnon-polar components thereof desired. A single-body soft gelatincapsule, for example, in oval, oblong or other shapes, typically isprovided, for example, in sizes from 3 to 22 US minims (1 US minim beingequal to 0.0616 mL or about 1/60 of a fluid dram (about one drop)). Aminim is a unit of volume occupied by a fluid or semi-fluid matrix suchas, for example, the volume occupied by a concentrate containingnon-polar ingredients. For example, an oblong or oval capsule that is4.0 minims in size can contain 0.246 mL of material, for example, aconcentrate containing non-polar ingredients. In another example, anoblong or oval capsule that is 8.0 minims in size can contain 0.493 mLof material, for example, a concentrate containing non-polaringredients. Capsule sizes are designated by convention as (000), (00),(0), (1), (2), (3), (4), and (5), with a larger number corresponding toa smaller size. For example, one teaspoon can fill approximately sevensize “0” capsules and about five size “00” capsules. Size “00” capsulesare generally the largest size utilized for human consumption. Soft gelscan contain, for example, at least 30, 40, 50, 60, 70, 80, 90, 100, 150,200, 300, 400, 500, 600, 800 or 1000 mg of the pre-gel composition.Dosage amount depends upon the non-polar components, a daily dosagethereof and the number of soft gels to be consumed per day. The soft gelcomposition can provide a single dose or a fractional dose.

The soft capsules can be manufactured, for example, according to theconventional methods listed above with the addition of a printed item onthe capsule. Examples of printed items include, but are not limited to,bandings, brandings, designations, identifications, images, and otherprinted items, and are exerted by methods well known in the art (see,e.g., U.S. Pat. Nos. 2,449,139; 2,623,494; 2,703,047; 2,688,775;3,124,840; 3,203,347; 3,333,031; and 5,246,635). A soft gel capsule, forexample, a soft gelatin capsule, that has been manufactured inaccordance with conventional methods an be characterized by severalproperties of the capsule, including, but not limited to, Bloom strengthand hardness. The Bloom test measures the strength of the gel capsule inwhich the majority is composed of gelatin, by determining the weight (ingrams) of a probe that is needed to deflect the surface of the gel 4 mmwithout puncturing the surface of the gel. Results of the Bloom test areexpressed in Bloom units and generally vary between 30-300 Bloom. Thespecific procedure of characterization by the Bloom method are wellknown to the skilled artisan. In other instances, the strength of thecapsule wall is measured by an alternative device that assesses theelasticity, integrity and/or strength of the gel capsule, including seamstrength. The optimal range for a characteristic soft gel, such as thesoft gel capsules described herewith, is 150-250. In addition to Bloomstrength, soft gel capsules can also be characterized by their hardness.The hardness of a soft gel capsule is largely determined by the ratio ofthe plasticizer component to gelatin. Following the drying processduring capsule manufacturing, a Bareiss Hardness tester, or anequivalent device, is used to measure the hardness of the soft gelcapsule. Measures of soft gel capsule integrity are essential forquality control prior to packaging; moreover, measurements that fallwithin acceptable ranges, such as values known to the skilled artisan,are used to predict and prevent failure during packaging.

Soft gel capsules, such as the soft gel capsules containing thenon-aqueous pre-gel concentrates containing non-polar ingredientsprovided herein, can be packaged in containers, for example packagingfor the soft gels can include, but is not limited to, plastic or glassor metal containers, or blister cards. Soft gel packaging can provideenhanced protection against various insults, including, but not limitedto, humidity, oxygen, light, and other toxicities. Plastic containerscan be made of any suitable plastic materials including, for example,high density polyethylene, polypropylene, and polyethyleneterephthalate, and can also include an integrated or separate desiccantand/or oxygen absorber. Glass bottles can be colored glass, inductionsealed, and have a plastic or metal lid. In some embodiments, thepackaging of soft gels in bottles can include bottles that are opaque,tamper-resistant, or tamper-evident. In some embodiments, the bottlescontain sufficient desiccant material to protect the soft gels fromdamage from increased water or humidity where the desiccant can beintegrated into the container, separate, or as a film.

In some examples, the soft gels compositions are packaged in containers.Containers used for packaging soft gels, such as the soft gelscontaining non-aqueous pre-gel concentrates containing non-polaringredients provided herein, can be filled with any number of soft gelcapsules. For example, a container can contain, for example, 10, 20, 30,40, 50, 60, 70, 80, 90, 100, 500, 1000, or more than 1000, soft gelcapsules, such as the soft gel capsules containing the non-aqueouspre-gel concentrates containing non-polar ingredients provided herein.In other examples, the soft gel compositions are packaged in blistercards. Blister cards used for packaging soft gels, such as the soft gelscontaining non-aqueous pre-gel concentrates containing non-polaringredients provided herein, can contain any number of soft gel tablets,e.g., a blister card can hold 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90,100, or more than 100 soft gel capsules, such as the soft gel capsulescontaining the non-aqueous pre-gel concentrates containing non-polaringredients provided herein. Blister cards can, for example, contain afoil backing as a barrier. Blister cards or packaging can include, forexample, triplex blister film of different types, such as standard andhigh barrier films, including, for example, triplex Flexafarm Sbc (e.g.,PVC 250 my+PE 25 my+PVDC 150 g/mq sbc grade) and Aquaba-PVC (e.g., PVC250 my+AQUABA 160 g/mq), Aclar, Alu-Alu formats, triple layer blisterfoil (OPA) with soft tempered aluminium in central position, otherlayers PVC and polyamide, and new generation multilayer blister combinedmaterials.

d. Formulating the Soft Gel Compositions

The provided non-aqueous pre-gel concentrates contain a high amount ofnon-aqueous solvent and have displayed advantageous properties afterencapsulation, such as encapsulation in a shell or coating, e.g., agelating shell or coating, to form a soft gel composition. For example,the soft gel compositions provided herein that contain a high amount ofnon-aqueous solvent have advantageous properties, such as, for example,the soft gel compositions contain a high amount of non-polar ingredientthat does not precipitate out of the composition. Additionally, the softgel compositions provided herein that contain a high amount of non-polaringredient display enhanced bioavailability of the non-polar ingredientsafter consumption, for example, human consumption, of the soft gelcomposition, as compared to tablets or powders.

The non-aqueous pre-gel concentrates provided herein are formulated suchthat encapsulation of a concentrate, for example, in a coating or shell,e.g., a gelatin coating or shell, yields a soft gel composition thatcontains a homogenous concentrate, i.e., a concentrate in which thenon-polar ingredients are dissolved in the non-aqueous solvent and donot precipitate out. The high solubility of the non-polar ingredients inthe non-aqueous solvent leads to advantageous properties, for example,enhanced bioavailability of the non-polar ingredients when the soft gelis consumed, for example, by a human.

A number of parameters of the pre-gel concentrates, includingingredients, their relative concentrations, and methods for making thepre-gel concentrates, affect the ability of the non-polar ingredients toremain in solution and not precipitate when a high concentration ofnon-polar ingredient is present. By extension, these parameters of thepre-gel concentrates also affect the advantageous properties of the softgel compositions, for example, the bioavailability of the non-polaringredients in the soft gel composition upon consumption, for example,human consumption.

Thus, the pre-gel concentrates are formulated such that afterencapsulation, the resulting soft gel composition displays one or moreadvantageous properties, for example, lack of phase separation and/orprecipitation over time, and/or enhanced bioavailability of thenon-polar ingredients. In one example, the advantageous property is theability of the provided pre-gel concentrates to yield soft gelcompositions that have a lack of precipitation of the non-polaringredients when encapsulated, for example, in a coating or shell. Inanother example, the advantageous property relates to the ability ofpre-gel concentrates to be encapsulated for human consumption, forexample, in a consumable shell or coating. In another example, it can beadvantageous that the pre-gel concentrate contains less than or equal toa particular concentration of one or more ingredients. In anotherexample, it can be advantageous that the pre-gel concentrates containsgreater than or equal to a particular concentration of one or moreingredients.

e. Ingredients and Concentration Ranges

Each of the provided soft gel compositions contains a pre-gelconcentrate encapsulated in a shell or coating, such as a gelatin shellor coating. The pre-gel concentrates, and thus, the encapsulated softgel compositions provided herein, contain one or more non-polaringredients, at least one surfactant, and one or more non-aqueoussolvents. Typically, encapsulation of a pre-gel concentrate to form asoft gel composition does not change or alter the identity orconcentration of the ingredients in the pre-gel concentrate, e.g., theidentity and concentration of ingredients in a particular pre-gelconcentrate remain the same in the corresponding soft gel compositionafter encapsulation.

Each of the provided soft gel compositions contains a non-polaringredient including, but not limited to, the exemplary non-polaringredients described herein above. Typically, the non-polar ingredientis or contains one or more non-polar compounds. The soft gelcompositions provided herein can contain one non-polar ingredient ormore than one non-polar ingredient, such as two, three, four, five, six,seven, eight, or more non-polar ingredients. The soft gel compositionsprovided herein can contain high amounts (i.e., concentrations) ofnon-polar ingredients, such as up to at or about 90 wt % non-polaringredients.

The soft gel compositions provided herein contain pre-gel concentratesthat contain one or more non-polar ingredients, where the total amountof non-polar ingredients is typically present in an amount as apercentage (%) by weight of the soft gel compositions (wt %), e.g., fromat or about 40 wt % to at or about 90 wt %, such as between or betweenabout 40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%, 40% and 65%,40% and 70%, 40% and 75%, 40% and 80%, 40% and 85%, 40% and 90%, 45% and50%, 45% and 55%, 45% and 60%, 45% and 65%, 45% and 70%, 45% and 75%,45% and 80%, 45% and 85%, 45% and 90%, 50% and 55%, 50% and 60%, 50% and65%, 50% and 70%, 50% and 75%, 50% and 80%, 50% and 85%, 50% and 90%,55% and 60%, 55% and 65%, 55% and 70%, 55% and 75%, 55% and 80%, 55% and85%, 55% and 90%, 60% and 65%, 60% and 70%, 60% and 75%, 60% and 80%,60% and 85%, 60% and 90%, 65% and 70%, 65% and 75%, 65% and 80%, 65% and85%, 65% and 90%, 70% and 75%, 70% and 80%, 70% and 85%, 70% and 90%,75% and 80%, 75% and 85%, 75% and 90%, 80% and 85%, 80% and 90%, and 85%and 90% non-polar ingredient by weight of the soft gel compositions.Exemplary concentrations of the total amount of non-polar ingredients inthe soft gel compositions are at or about 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, and 90% (wt %) of the soft gel compositions.

Each of the provided soft gel compositions contain pre-gel concentratesthat contain at least one surfactant that is a polyethylene glycolderivative of vitamin E, for example, TPGS, TPGS analogs, TPGS homologsand TPGS derivatives described herein. The surfactant typically has anHLB value of between 12 or about 12 and 20 or about 20, for example, 12,13, 14, 15, 16, 17, 18, 19 or 20, or about 12, about 13, about 14, about15, about 16, about 17, about 18, about 19 or about 20, typicallybetween at or about 12 and at or about 14. For example, TPGS, such asthe TPGS described herein, has an HLB value of about 13.

The polyethylene glycol derivative of vitamin E, e.g., TPGS, istypically present in an amount as a percentage (%) by weight of the softgel compositions (wt %), e.g., from at or about 5% to at or about 40%,such as 5% to 10%, 5% to 15%, 5% to 20%, 5% to 25%, 5% to 30%, 5% to35%, 5% to 40%, 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to35%, 10% to 40%, 15% to 20%, 15% to 25%, 15% to 30%, 15% to 35%, 15% to40%, 20% to 25%, 20% to 30%, 20% to 35%, 20% to 40%, 25% to 30%, 25% to35%, 25% to 40%, 30% to 35%, 30% to 40%, 30% to 30%, 30% to 35%, 30% to40%, and 35% to 40%, by weight of the soft gel compositions. Exemplaryconcentrations of the polyethylene glycol derivative of vitamin E, e.g.,TPGS, in the soft gel compositions are at or about 5%, 7%, 10%, 12%,15%, 17%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, and 40% (wt %) of thesoft gel compositions.

The soft gel compositions contain pre-gel concentrates that contain oneor more non-aqueous solvents. Typically, the non-aqueous solventsinclude those that are insoluble or only partially soluble in water.Exemplary non-aqueous solvents include alcohols, such as aromaticalcohols, e.g., benzyl alcohol, alcohol derivatives, such as esters,e.g., benzyl benzoate, and hydrocarbons, such as cyclic hydrocarbons,e.g., d-limonene. In one example, the soft gel composition containsbenzyl alcohol as a non-aqueous solvent. In another example, the softgel composition contains a mixture of benzyl alcohol and d-limonene asthe non-aqueous solvents. The soft gel compositions provided herein cancontain one non-aqueous solvent or more than one non-aqueous solvent,such as two, three, four, five, or more non-aqueous solvents.

The soft gel compositions provided herein contain pre-gel concentratesthat contain one or more non-aqueous solvents, where the total amount ofnon-aqueous solvent is typically present in an amount as a percentage(%) by weight of the soft gel compositions (wt %), e.g., from at orabout 5 wt % to at or about 20 wt %, such as between or between about 5%and 7%, 5% and 10%, 5% and 12%, 5% and 15%, 5% and 17%, 5% and 20%, 7%and 10%, 7% and 12%, 7% and 15%, 7% and 17%, 7% and 20%, 10% and 12%,10% and 15%, 10% and 17%, 10% and 20%, 12% and 15%, 12% and 17%, 12% and20%, 15% and 17%, 15% and 20%, and 17% and 20% non-aqueous solvent(s) byweight of the soft gel compositions. Exemplary concentrations of thetotal amount of non-aqueous solvent(s) in the soft gel compositions areat or about 5%, 7%, 10%, 12%, 15%, 17%, and 20% (wt %) of the soft gelcomposition.

f. Exemplary Dosages and Administration of the Soft Gel Compositions

The soft gel compositions provided herein that contain non-aqueouspre-gel concentrates containing non-polar ingredients, can beformulated, for example, for single dosage (direct) administration,multiple dosage administration, or for dilution or other modification.The concentration of the non-polar ingredients in the soft gelcompositions is typically effective for delivery of an amount, uponadministration, that is effective for the intended treatment or benefit.Those of skill in the art can readily formulate a composition foradministration in accord with the methods herein. For example, toformulate a soft gel composition, the weight fraction of a non-polaringredient is dissolved, suspended, dispersed, or otherwise mixed, forexample as detailed in the Examples, below, and then the compositionencapsulated by a shell or coating, such as a soft shell or coating,e.g., gelatin, and the resulting soft gel capsule is utilized as avehicle for delivering an effective concentration of non-polaringredient. For example, an effective concentration of non-polaringredient can be delivered via the soft gel to a human, for example, byconsumption of the soft gel composition.

The precise amount or dose of the non-polar ingredient administered viathe soft gel composition depends upon one or more considerations,including, for example, the condition to be treated, the benefit to beconferred, the weight and general state of the subject, and/or theparticular characteristics of the subject. If necessary, a particulardosage and duration and treatment protocol can be empirically determinedor extrapolated. For example, exemplary doses of non-polar ingredients,such as the non-polar ingredients provided herein, if necessary, can beused as a starting point to determine appropriate dosages for aparticular subject and condition or benefit.

The soft gel compositions containing pre-gel concentrates that containnon-polar ingredients can be formulated so that the dose of non-polaringredient contained within a single soft gel capsule is from, forexample, 100 g or about 100 g to 2000 g or about 2000 g, or 200 g orabout 200 g to 2000 g or about 2000 g, such as at or at least about 100g, 150 g, 200 g, 250 g, 300 g, 350 g, 400 g, 450 g, 500 g, 600 g, 700 g,800 g, 900 g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g,1700 g, 1800 g, 1900 g, or 2000 g, for direct administration.

Typically, the concentration of non-polar ingredient is not more than90% or about 90% of the weight of the soft gel composition, for example,between 40% or about 40% and 90% or about 90% of the weight of the softgel composition. For example, when the non-polar ingredient isadministered as a component of the pre-gel concentrate encapsulated by ashell or coating, e.g., a gelatin shell or coating, as described herein,the non-polar ingredient is administered at a concentration of between40% or about 40% and 90% or about 90%, although more dilute or higherconcentrations can be used. Generally, the level of non-polar ingredientcan be increased or decreased according to the judgment of a person ofskill in the art. The amount of the remaining ingredients can beadjusted as needed.

In the methods described herein, soft gel compositions containingnon-aqueous pre-gel concentrates containing non-polar ingredients, suchas the soft gel compositions described herein, can be administered to asubject for treating a variety of conditions or conferring a particularbeneficial effect. In particular, the soft gel compositions providedherein are intended for use in methods in which other pharmaceuticals,nutraceuticals and/or dietary supplements, such as known treatments, canbe used to convey a benefit to the subject. The non-polar ingredientscontained within the soft gel compositions provided herein are typicallyincluded in an amount sufficient to confer a beneficial effect in theabsence of undesirable side effects on the subject. The amount ofnon-polar ingredient to be administered can be determined by one ofskill in the art. The precise dosage, which can be determinedempirically, can depend on the particular composition, the type ofcondition to be treated and the seriousness of the condition, the typeof benefit to be conferred, in addition to other characteristics knownto those of skill in the art.

4. Powders and Pre-Spray Emulsions

The high dimer-containing water-soluble vitamin E derivatives, such asthe PEG derivatives of vitamin E, particularly the high dimer-containingTPGS mixtures, are included in emulsion compositions that are fordrying, such as by spray-drying, to form powders. The pre-sprayemulsions include all of the ingredients in the powders and additionallya polar compound, such as water, which is removed by spray drying,evaporation or other drying process. The ingredients include thenon-polar ingredient(s), the high dimer-containing PEG derivative ofvitamin E, in particular, a TPGS mixture, a sugar fatty acid, a binder,such as a maltodextrin, and other optional ingredients, such asstabilizers, such as a carbonate or bicarbonate, antioxidants, such asascorbic acid or a co-enzyme Q-containing product, and/or an ingestibleacid. The emulsions are prepared and then dried to produce the powders.

Typically, drying an emulsion with a high oil load results in a productthat is not free-flowing and is more like a sludge than a powder.Provided are water-soluble powder products that contain highconcentrations (more than 20%, and particularly, more than 25%, 27%,30%, 35%, 40%, 45%, 47%, or 50%, by weight of the composition) ofnon-polar ingredients. In order to produce powders for spray drying, itis necessary to include a threshold amount of solids for forming thepowder. To achieve this, the TPGS is reduced in amount, and sugar fattyacid esters, such as SFAEs, are added in its place and in addition to orin place of a binder, such as a dextrin. In the absence of the addedSFAE, when dried, the emulsions, and particularly the emulsions withhigher amounts of non-polar ingredient, do not form a dry free-flowingpowder, but form a sludge-like oil with too high a moisture content. Thedry powders are added in any desired amount to a beverage, particularlyan aqueous beverage, and/or to a food, to supplement the beverage or asa way to deliver the non-polar ingredient(s) therein.

The powders contain sugar fatty acids in place of or in addition to thebinders, such as a dextrin, generally used to produce powders fromemulsions. The resulting powders are free-flowing (not sticky orsludge-like) and water-soluble. Also provided are pre-spray emulsionsfrom which the powders are produced. Addition of a sucrose (or othersugar) fatty acid ester in place of maltodextrin or other such binder ina pre-spray emulsion permits production of free-flowing dry powders witha higher concentration of non-polar ingredients than previouslyavailable.

The pre-spray emulsions also can include additional ingredients, such asstabilizers, include carbonates and bicarbonates, as described above,and antioxidants. The sugar fatty acid esters, such as SFAEs, and thecarbonate, such as KHCO₃, improve the stability of the powders and alsothe resulting beverages and foods into which the powders are dissolved.The sugar fatty acid esters, such as SFAEs, act as emulsifiers in thepre-spray emulsion and powders, and also act as a solid for drying thepre-spray emulsions to produce the powders. Compared to prior artpowders prepared from emulsions containing a PEG derivative of vitamin Eand/or other such surfactants that are not solids, such as TPGS alone,only contribute to stability of the pre-spray emulsion, but do notcontribute to formation of a powder. By including the sugar fatty acidesters, such as SFAEs, the properties of the powders are improved, andhigher levels of non-polar ingredients can be included.

Exemplary pre-spray emulsions and powders are described in the examplesand below. All contain up to about or at 60% non-polar ingredient; 1-10%TPGS; and a binder and sugar fatty acid esters, such as SFAE andmaltodextrin (or other such binder). Additional optional ingredientsinclude stabilizers, emulsifiers and antioxidants. For example, onepowder described herein includes: 45-55% oil/non polar compound(s); 1-2%TPGS; 15-20% SFAE (emulsifier and binder); 3-10% carbonate, such asKHCO₃, which serves as an antioxidant, binder and keeps the powder dryand/or acts as a leavener); 15-20% green tea extract, which contains 50%EGCG powder (antioxidant); 1-2% saponin (quillaja bark; emulsifier); and0.1-0.2% Saladizer® (thickener and emulsifier). Another exemplary powdercontains 55-60% oil/non polar compound(s); 1-2% TPGS (emulsifier); 5-10%SFAE (emulsifier and binder); 3-10% carbonate, such as KHCO₃(antioxidant, binder and keeps the powder dry or acts as a leavener);15-25% whey protein/gelatin powder (binder); 1-2% saponin (quillajabark; emulsifier) and 0.1-0.2% Saladizer® (thickener and emulsifier).These amounts and compositions are exemplary only. Further examples aredescribed below. It is understood that for purposes herein, thewater-soluble vitamin E derivative, such as a PEG derivative of vitaminE, such as TPGS, is a high dimer-containing form described and definedabove. Such description is incorporated into this section by reference.

Provided are pre-spray emulsions, which contain the non-polaringredient(s) as described herein above, the high dimer-containingwater-soluble vitamin E derivative mixture, such as a PEG derivative ofvitamin E, such as TPGS, as described and defined above, and thenon-polar ingredient, as well as the sugar fatty acid esters, such as anSFAE or mixture thereof, and a binder, such as maltodextrin, whey andothers described herein and/or known to those of skill in the art, andany other ingredients to be included in the powder. As described below,these are combined to form a pre-spray emulsion which is then dried toform a powder. To form the powder, the pre-spray emulsion can be dried,and then dissolved in an aqueous medium, such as water, and dried again.

a. Pre-Spray Emulsions Containing Non-Polar Ingredients

Provided herein are pre-spray emulsions that contain the pre-emulsionconcentrates containing non-polar ingredients dispersed in aqueousliquid and have desirable properties, including improved clarity,stability, smell and taste. The provided emulsions (and methods formaking the emulsions) can be used to formulate any non-polar ingredientin aqueous compositions, including the non-polar ingredients (e.g.,non-polar ingredients that are or contain non-polar compounds) describedherein and other known non-polar ingredients.

In general, emulsions (e.g., oil-in-water emulsions) are colloidaldispersions of two immiscible liquids (e.g., oil and water or otheraqueous liquid), containing a continuous and a dispersed phase.Emulsions can be used to disperse non-polar ingredients in aqueousliquids. In an oil-in-water emulsion, the dispersed phase is an oilphase and the continuous phase is an aqueous (water) phase. There is aneed for emulsions (e.g., oil-in-water emulsions) containing non-polaringredients in aqueous liquids and methods and compositions forgenerating products, such as the water-soluble powders, that arefree-flowing, i.e., not sticky. In particular, emulsions are needed thatare more suitable and desirable for human consumption of the non-polaringredients, for example, beverages. For example, emulsions havingimproved clarity (e.g., small particle size, low turbidity), stability(e.g., lack of separation), taste and smell, that can form powders thatare free-flowing, i.e., not sticky, and water-soluble are providedherein.

Typically, the provided emulsions containing the concentrates containingnon-polar ingredients are nanoemulsions, which are emulsions havingdispersed droplets (particles) with diameters less than 1000 nm or lessthan about 1000 nm, typically, less than 500 nm or less than about 500nm, typically less than 300 nm or about 300 nm, typically less than 250or less than about 250 nm, typically less than 200 nm or less than about200 nm, for example, less than or less than about 5, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200nm. Typically, the provided nanoemulsion compositions are oil-in-waternanoemulsions, containing the non-polar ingredients dispersed in aqueousliquid.

The provided emulsion compositions are stabilized by one or moresurfactants and/or co-surfactants and/or emulsion stabilizers.Surfactants form an interfacial film in the emulsion, between the oiland water phase, providing stability. Typically, the nanoemulsions ofthe provided compositions contain micelles, in which one or moresurfactant surrounds the non-polar ingredient. The micelles aredispersed in the water phase.

The provided pre-spray emulsions contain the pre-emulsion concentratescontaining non-polar ingredients, which can be spray-dried to providenon-polar ingredients in a powder, such as free-flowing, water-solublepowder. The pre-spray emulsions can be made using any concentratecontaining non-polar ingredients, a sugar fatty acid ester, and apolyalkylene glycol derivative of vitamin, such as the pre-emulsionconcentrates provided herein.

i. Formulating the Pre-Spray Emulsions

In the provided methods, the pre-spray emulsions are formulated byselecting ingredients and concentration ratios of the ingredients thatyield compositions having one or more desired properties. Theingredients include a concentrate that contains non-polar ingredientsand a polyalkylene glycol vitamin E derivative, e.g., a highdimer-containing TPGS, a surfactant, such as a sugar fatty acid ester,e.g., sucrose fatty acid ester; and a polar solvent, e.g., water. Insome examples, the pre-spray emulsions further include one or more of astabilizer, a binder, e.g., maltodextrin, a co-surfactant, an emulsionstabilizer, and a pH adjuster. In the provided emulsions, a surfactant,such as a sugar fatty acid ester, e.g., sucrose fatty acid ester, ispresent in place of or in combination with a binder, e.g., maltodextrin.For example, the pre-spray emulsions provided herein can contain asurfactant, such as such as a sugar fatty acid ester, e.g., sucrosefatty acid ester, and not contain a binder, e.g., maltodextrin. In otherexamples, the pre-spray emulsions provided herein contain a mixture ofsurfactant, such as a sugar fatty acid ester, e.g., sucrose fatty acidester, and binder, e.g., maltodextrin.

The pre-spray emulsions provided herein contain high concentrations ofnon-polar ingredients, for example, at least 5%, 7%, 10%, 12%, 15%, 20%,25%, 30% or more non-polar ingredients, such that when the emulsion isdried the resulting powder includes up to as much as 60% non-polaringredient. The emulsions are formulated such that drying the emulsion,e.g., spray drying, yields a powder composition that contains highconcentrations of non-polar ingredient, yet is free-flowing, i.e., notsticky, and water-soluble. The emulsion dry to form a free-flowing,i.e., not sticky or sludgy, powder even where a high concentration ofnon-polar ingredient is present.

ii. Exemplary Ingredients and Typical Concentration Ranges

(a) Pre-Emulsion Concentrates

Each pre-spray emulsion provided herein contains a pre-emulsionconcentrate, such as the pre-emulsion concentrates provided herein, thatcontain non-polar ingredients that are or contain non-polar compoundsand a polyalkylene glycol derivative of vitamin E, for example, apolyethylene glycol derivative of vitamin, e.g., TPGS. In some examples,the pre-emulsion concentrate contains a preservative, for example,benzyl alcohol.

The pre-emulsion concentrates used in formulating the pre-sprayemulsions contain between or between about 30 wt % and 99 wt % non-polaringredient, typically at least 40 wt %, or at least 50 wt %, or more,such as at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%non-polar ingredient, by weight, of the pre-emulsion concentrate. Whenformulating the pre-spray emulsions provided herein that contain thepre-emulsion concentrates containing between or between about 30 wt %and 99 wt % non-polar ingredients, the emulsions will contain, forexample, between or between about 1 wt % and 40 wt % concentrate, suchas between or between about 1% and 5%, 1% and 10%, 1% and 15%, 1% and20%, 1% and 25%, 1% and 30%, 1% and 35%, 1% and 40%, 5% and 10%, 5% and15%, 5% and 20%, 5% and 25%, 5% and 30%, 5% and 35%, 5% and 40%, 10% and15%, 10% and 20%, 10% and 25%, 10% and 30%, 10% and 35%, 10% and 40%,15% and 20%, 15% and 25%, 15% and 30%, 15% and 35%, 15% and 40%, 20% and25%, 20% and 30%, 20% and 35%, 20% and 40%, 25% and 30%, 25% and 35%,25% and 40%, 30% and 35%, 30% and 40%, and 35% and 40% concentratecontaining non-polar ingredients, by weight, of the emulsion. Exemplaryconcentrations of the total amount of concentrate containing non-polaringredients in the emulsions are at or about 5%, 7%, 10%, 12%, 15%, 17%,and 20% (wt %) of the emulsion. By extension, the amount of non-polaringredient present in the pre-spray emulsions is typically between orbetween about 5 wt % and 30 wt % of the emulsion, for example, betweenor between about 5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and30%, 10% and 15%, 10% and 20%, 10% and 25%, 10% and 30%, 15% and 20%,15% and 25%, 15% and 30%, 20% and 25%, 20% and 30%, and 25% and 30%non-polar ingredient, by weight of the pre-spray emulsion.

(b) Surfactants

The provided pre-spray emulsions contain surfactants. In particular, thehigh dimer-containing water-soluble vitamin E derivative, such as a PEGderivative of vitamin E, particularly the high dimer-containing TPGS asdescribed above. Additionally, the compositions include sugar fatty acidesters, such as one or more SFAEs. In the provided methods for producingthe emulsions, the surfactant is added to the water phase, the oilphase, or to the water and the oil phase. The emulsions further cancontain one or more co-surfactants or emulsifiers. Typically, thesurfactants are natural surfactants, for example, a surfactant that isG.R.A.S. (generally recognized as safe) by the FDA and/or Koshercertified. In an exemplary embodiment, the surfactant is a sugar-derivedsurfactant, for example, a sugar fatty acid ester, e.g., sucrose fattyacid ester.

Exemplary of surfactants, in addition to the high dimer-containingwater-soluble vitamin E derivative compositions, such as a TPGS, and thesugar fatty acid esters, such as used in the provided methods andcompositions, are other surfactants having an HLB value of between 12 orabout 12 and 20 or about 20, for example, 12, 13, 14, 15, 16, 17, 18,19, 20, about 12, about 13, about 14, about 15, about 16, about 17,about 18, about 19 or about 20. The surfactants typically are, andtypically have an HLB value between at or about 12 and at or about 20.

Particular examples of suitable sugar fatty acid esters for use in theprovided compositions include the sugar derived surfactants, includingfatty acid esters of sugars and sugar derivatives. For example, sugarfatty acid esters include fatty acid esters of sucrose, glucose, maltoseand other sugars, esterified to fatty acids of varying lengths (e.g.,varying numbers of carbons). The fatty acids typically have carbonchains between 8 and 28 carbons in length, and typically between 8 and20, or between 8 and 18 or between 12 and 18, such as, but not limitedto, stearic acid (18 carbons), oleic acid (18 carbons), palmitic acid(16 carbons), myristic acid (14 carbons) and lauric acid (12 carbons).Typically, the sugar ester surfactants are sucrose ester surfactants,typically sucrose fatty acid ester surfactants.

The pre-spray emulsions provided herein contain a surfactant, such as asugar fatty acid ester, e.g., sucrose fatty acid ester, where the totalamount of surfactant, e.g., sucrose fatty acid ester, is typicallypresent in an amount as a percentage (%) by weight of the emulsion (wt%), e.g., from at or about 1 wt % to at or about 20 wt %, such asbetween or between about 1% and 3%, 1% and 5%, 1% and 7%, 1% and 10%, 1%and 12%, 1% and 15%, 1% and 17%, 1% and 20%, 3% and 5%, 3% and 7%, 3%and 10%, 3% and 12%, 3% and 15%, 3% and 17%, 3% and 20%, 5% and 7%, 5%and 10%, 5% and 12%, 5% and 15%, 5% and 17%, 5% and 20%, 7% and 10%, 7%and 12%, 7% and 15%, 7% and 17%, 7% and 20%, 10% and 12%, 10% and 15%,10% and 17%, 10% and 20%, 12% and 15%, 12% and 17%, 12% and 20%, 15% and17%, 15% and 20%, and 17% and 20%, sugar fatty acid ester, e.g., sucrosefatty acid ester, by weight of the soft gel compositions. Exemplaryconcentrations of the total amount of sugar fatty acid ester, e.g.,sucrose fatty acid ester in the pre-spray emulsions are at or about 1%,3%, 5%, 7%, 10%, 12%, 15%, 17%, and 20% (wt %) of the pre-sprayemulsions.

(1) Sucrose Fatty Acid Ester Surfactants

Sucrose fatty acid ester surfactants contain one or more sucrose fattyacid esters, which are non-ionic surfactants that contain sucrose in thehydrophilic portions and fatty acids in the hydrophobic portions. Thesucrose fatty acid esters can be made by well-known methods (see, forexample, U.S. Pat. Nos. 3,480,616, 3,644,333, 3,714,144, 4,710,567,4,898,935, 4,996,309, 4,995,911, 5,011,922 and 5,017,697 andInternational Patent Application Publication No. WO 2007/082149),typically in an esterification reaction as described below.

Because sucrose contains eight hydroxy (—OH) groups, the esterificationreaction can join the sucrose molecule to one fatty acid molecule, orcan join it to a plurality of, fatty acid molecules, producing differentdegrees of esterification, e.g., mono-, di-, tri- and poly-(up to octa-)fatty acid esters, but primarily mono-, di-, and/or tri-esters. Thedegree of esterification can depend on conditions of esterification. Theesterification reaction can be carried out with a single type of fattyacid, or a plurality of fatty acids, such as fatty acids with varyingcarbon chain lengths, branched and linear fatty acids, and/or saturatedor unsaturated fatty acids. The esterification reaction with a singlefatty acid can produce a single ester, and typically forms more than oneester, such as mono- di-, tri- and/or poly-esters, formed from onereaction. The relative amounts of mono- di- tri- and/or poly-esters candepend on reaction conditions.

The fatty acid in the sucrose fatty acid ester can be any fatty acid,and can contain between 4 and 28 carbon atoms, typically between 8 and28 carbon atoms, and typically between 8 and 25 carbon atoms, such asbetween 8 and 18 carbon atoms, such as 8, 9, 10, 11, 12, 13, 14, 15, 16,17 and 18 carbon atoms. The fatty acid can be synthetic or naturallyoccurring, and include linear and branched fatty acids. The fatty acidsinclude, but are not limited to, myristic acid, palmitic acid, stearicacid, oleic acid, caproic acid, capric acid, myristic acid, decanoicacid and pelargonic acid.

Thus, the sucrose fatty acid ester surfactants include sucrosemonoesters, diesters, triesters and polyesters, and mixtures thereof,and typically contain sucrose monoesters. The sucrose fatty acid estersurfactants include single fatty acid esters and also includehomogeneous mixtures of sucrose esters, containing members withdifferent lengths of fatty acid carbon chain and/or members withdifferent degrees of esterification. For example, the sucrose fatty acidester surfactants include mixtures of monoesters, diesters, triesters,and/or polyesters. The sugar ester surfactants further include sucrosefatty acid ester analogs and homologs and mixtures thereof.

Sucrose fatty acid esters are compounds having the following formulashown below:

where each of X¹, X², X³, X⁴, X⁵, X⁶, X⁷ and X⁸ independently is:

a hydroxyl (—OH) group, or

where:

each R is an alkyl group having 3-27 carbon atoms; and

when more than one of X¹, X², X³, X⁴, X⁶, X⁷ and X⁸ is

each R can be a different alkyl group (e.g., having different number ofcarbon atoms and/or different saturation), or can be the same alkylgroup.

Typically, in the provided sucrose fatty acid ester surfactants, each Rhas between 7 and 27 carbon atoms, and typically between 7 and 19 atoms,such as 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 carbon atomsor between 7 and 17 carbon atoms.

An alkyl group can be a straight chain or branched alkyl group, can besubstituted or unsubstituted, and can be a saturated “saturated alkylgroup,” meaning that it does not contain any alkene or alkyne groups; oran “unsaturated alkyl group,” meaning that it contains at least onealkene or alkyne group. An alkyl group that includes at least onecarbon-carbon double bond (C═C) also is referred to by the term“alkenyl,” and alkenyl groups optionally can be substituted. An alkylgroup that includes at least one carbon-carbon triple bond (C≡C) also isreferred to by the term “alkynyl,” and alkynyl groups optionally can besubstituted.

Typically, the sucrose fatty acid ester surfactants contain sucrosefatty acid monoesters, having the structure set forth below, where oneof X¹, X², X³, X⁴, X⁵, X⁶, X⁷ and X⁸ (typically X¹) is

and the other seven of X¹, X², X³, X⁴, X⁶, X⁷ and X⁸ are each,independently, —OH. An exemplary monoester has the following structure:

where R is an alkyl group having 3-27 carbons, and typically 7-27carbons.

The sucrose fatty acid esters include blends of sucrose fatty acidesters, which typically include monoesters, and can also includediesters, triesters and polyesters, which have structures according toScheme V, above, where two (diesters), three (triesters) or more(polyesters) of X¹, X², X³, X⁴, X⁵, X⁶, X⁷ and X⁸, (and typically X¹ andX⁸) independently, are

In general, sucrose fatty acid esters, including mixtures of sucrosefatty acid esters, can have varying HLB values, such as HLB valuesranging from at or about 1 to at or about 20. The HLB value of thesucrose fatty acid ester generally depends on the degree ofesterification (e.g., the average degree of esterification in a mixtureof different esters). Typically, the lower the degree of esterification(e.g., average degree), the higher the HLB value of the sucrose fattyacid ester or mixture thereof. Exemplary sucrose esters include sucrosedistearate (HLB=3), sucrose distearate/monostearate (HLB 12), sucrosedipalmitate (HLB=7.4); sucrose monostearate (HLB=15), sucrosemonopalmitate (HLB>10); Sucrose monolaurate (HLB 15). Typically, thesucrose fatty acid ester surfactants in the provided compositions havean HLB value of between at or about 14 and at or about 20, such as at orabout 14, 15, 16, 17, 18, 19, or 20, and typically between at or about14 and at or about 18, such as, but not limited to, HLB values of at orabout 15, 16 and 17, such as, for example, sucrose ester surfactantsincluding sucrose monopalmitate, sucrose monolaurate and sucrosemonostearate.

The sugar ester surfactants include sucrose ester blends, for example,sucrose ester mixtures containing a specified amount (e.g., percent, byweight) of sucrose monoesters. Exemplary surfactants include sucroseester mixtures having at least at or about 50%, by weight (w/w),monoester, such as at or about or at least at or about 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%, by weight (w/w), sucrosemonoesters, and typically at least at or about 60%, by weight or atleast at or about 70%, by weight (w/w), monoesters. The surfactantsinclude mixtures of sucrose esters containing at least at or about 50%sucrose monoesters, mixtures of sucrose esters containing at least at orabout 60% sucrose monoesters, mixtures of sucrose esters containing atleast at or about 70% sucrose monoesters, mixtures of sucrose esterscontaining at least at or about 80% sucrose monoesters, and mixtures ofsucrose esters containing at least at or about 90% sucrose monoesters,for example, mixtures containing at or about 72% sucrose monoesters, ator about 61% sucrose monoesters, or at or about 90% sucrose monoesters.

The sucrose fatty acid ester surfactants include sucrose fatty acidmonoesters, such as sucrose monocaprylate, sucrose monodecanoate,sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate,sucrose monostearate, sucrose monopelargonate, sucrose monoundecanoate,sucrose monotridecanoate, sucrose monopentadecanoate and sucrosemonoheptadecanoate. The sucrose fatty acid esters further includemixtures containing varying percentages of monoesters, diesters,triesters and polyesters, such as, but not limited to, a mixture havingat or about 72% monoesters, 23% diesters, 5% triesters and 0%polyesters; a mixture having at or about 61% monoesters, 30% diesters,7% triesters, and 2% polyesters; and a mixtures having at or about 52%monoesters, 36% diesters, 10% triesters and 2% polyesters.

The sucrose fatty acid ester surfactants include sucrose fatty acidesters sold under the trade name DK Ester®, produced by Dai-Ichi KogyoSeiyaku Co., Ltd of Japan (which, in some examples, can be producedaccording to the methods described in U.S. Pat. Nos. 4,898,935,4,996,309, 4,995,911, 5,011,922 and 5,017,697, and distributed throughMontello Inc., Tulsa, Okla., such as the F-160 and F-140 grade esterssold under the trade name DK Ester®, and sucrose esters sold under thetrade name SURFHOPE® SE PHARMA, by Mitsubishi-Kagaku Foods Corporation,distributed by Mitsubishi Chemical Performance Polymers, Inc. Thesesucrose fatty acid esters are mixtures of esters with different degreesof esterification. The sucrose fatty acid esters further include Ryotosugar esters, which are food-grade esters sold by Mitsubishi-KagakuFoods Corporation, distributed by Mitsubishi Chemical PerformancePolymers, Inc. Exemplary sucrose fatty acid esters sold under the tradename DK Ester®, and those sold under the trade name SURFHOPE® SE PHARMAand Ryoto sugar esters, are listed in the table below. The table liststhe average degree of esterification or the fatty acid compositionwithin the mixture, and the HLB of the sucrose fatty acid estersurfactant. Any of the surfactants in the table below can be used.Typically, the surfactant (e.g., a surfactant listed in the tablebelow), has an HLB value between at or about 12 and at or about 20,typically between at or about 15 and at or about 18, e.g., but notlimited to, those surfactants in the table having an HLB of 15 or 16,such as the sucrose fatty acid ester surfactant sold under the name DKESTER® F-160, produced by Dai-Ichi Kogyo Seiyaku Co., Ltd of Japan, anddistributed through Montello Inc., Tulsa, Okla. Other exemplary sucrosefatty acid ester surfactants are described in Youan et al., AAPSPharmaSci 2003; 5(2) Article 22; 1-9 and in Okamoto et al., Biol. Pharm.Bull. 28(9): 1689-1694 (2005).

Exemplary Sucrose Fatty Acid Ester (SFAE) Surfactants

Average Distribution (by weight) Sucrose Fatty Degree of Fatty acid ofEster Acid Ester Esterification composition H.L.B. Mono:Di:Tri:Poly DKEster ® F-160 1.23 16 72% monoester; 23% diester; 5% triester DK Ester ®F-140 1.35 13 61% monoester; 30% diester; 7% triester; 2% polyester DKEster ® F-110 1.48 11 52% monoester; 36% diester; 10% triester; 2%polyester DK Ester ® F-90 1.53 9.5 45% monoester; 39% diester; 12%triester; 4% polyester DK Ester ® F-70 1.60 8 39% monoester; 45%diester; 12% triester; 4% polyester DK Ester ® F-50 1.69 6 34%monoester; 46% diester; 17% triester; 3% polyester DK Ester ® F-20W 3.112 11% monoester; 21% diester; 14% triester; 54% polyester DK Ester ®F-10 4.85 1 0% monoester; 5% diester; 11% triester; 84% polyesterSURFHOPE ® SE C12 (100%) 5 32% monoester; PHARMA 68%di-/tri-/poly-esters J-1205 SURFHOPE ® SE C12 (100%) 16 81% monoester;PHARMA 19% di-/tri-/poly-esters J-1216 SURFHOPE ® SE C16 (80%); C18 1679% monoester; PHARMA (20%) 21% di-/tri-/poly-esters J-1616 SURFHOPE ®SE C16 (70%); C18 5 30% monoester; PHARMA (30%) 70% di-/tri-/poly-estersJ-1805 SURFHOPE ® SE C16 (70%); C18 7 41% monoester; PHARMA (30%) 59%di-/tri-/poly-esters J-1807 SURFHOPE ® SE C16 (70%); C18 16 75%monoester; PHARMA (30%) 25% di-/tri-/poly-esters J-1816 SURFHOPE ® SESucrose stearate 3 Approximately 20% PHARMA (approximately monoester;approximately D-1803 70% stearate) 80% di-/tri-/poly-esters SURFHOPE ®SE Sucrose stearate 3 20% monoester; PHARMA (70% stearate) 80%di-/tri-/poly-esters D-1803F SURFHOPE ® SE Sucrose stearate 5 30%monoester; PHARMA (70% stearate) 70% di-/tri-/poly-esters D-1805SURFHOPE ® SE Sucrose stearate 7 40% monoester; PHARMA (70% stearate)60% di-/tri-/poly-esters D-1807 SURFHOPE ® SE Sucrose stearate 9 50%monoester; PHARMA (70% stearate) 50% di-/tri-/poly-esters D-1809SURFHOPE ® SE Sucrose stearate 11 55% monoester; PHARMA (70% stearate)45% di-/tri-/poly-esters D-1811 SURFHOPE ® SE Sucrose stearate 11 55%monoester; PHARMA (70% stearate) 45% di-/tri-/poly-esters D-1811FSURFHOPE ® SE Sucrose stearate 15 70% monoester; PHARMA (70% stearate)30% di-/tri-/poly-esters D-1815 SURFHOPE ® SE Sucrose stearate 16 75%monoester; PHARMA (70% stearate) 25% di-/tri-/poly-esters D-1816SURFHOPE ® SE Sucrose palmitate 15 70% monoester; PHARMA (80% palmitate)30% di-/tri-/poly-esters D-1615 SURFHOPE ® SE Sucrose palmitate 16 80%monoester; PHARMA (80% palmitate) 20% di-/tri-/poly-esters D-1616SURFHOPE ® SE Sucrose laurate 16 80% monoester; PHARMA (95% laurate) 20%di-/tri-/poly-esters D-1216 Ryoto S-970 Sucrose stearate 9 50% monoesterRyoto S-1170 Sucrose stearate 11 55% monoester Ryoto S-1570 Sucrosestearate 15 70% monoester Ryoto S-1670 Sucrose stearate 16 75% monoesterRyoto P-1570 Sucrose palmitate 15 70% monoester Ryoto P-1670 Sucrosepalmitate 16 80% monoester Ryoto LWA-1570 Sucrose laurate 15 70%monoester Ryoto L-1695 Sucrose laurate 16 80% monoester Ryoto OWA-1570Sucrose oleate 15 70% monoester

As noted above, methods for producing sucrose esters are well known(see, for example, U.S. Pat. Nos. 3,480,616, 3,644,333, 3,714,144,4,710,567, 4,898,935, 4,996,309, 4,995,911, 5,011,922 and 5,017,697 andInternational Patent Application, Publication No. WO 2007/082149). Thesucrose fatty acid surfactants can be produced by any well-known method,and typically in an esterification reaction, for example, by reactingsucrose with a methyl ester of the desired fatty acid, such as a solventprocess, where sucrose is reacted with a methyl ester of a fatty acid inthe presence of a catalyst (e.g., potassium carbonate) and an organicsolvent (e.g., dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO)),followed by purification, or in an aqueous medium process, where sucroseis mixed in a molten mixture with fatty acid salt using water without anorganic solvent and then reacted with a higher fatty acid methyl esterin the presence of a catalyst, followed by purification, and such as byany of the methods described in International Patent ApplicationPublication No. WO 2007/082149, whereby a sucrose molecule (which is adisaccharide containing one six-carbon aldo-sugar glucose linked to afive-carbon keto-sugar fructose, having the formula: C12H22O11) isjoined to one or more fatty acids.

For example, the sucrose fatty acid ester can be produced byesterification using dimethyl formamide (DMF) as a solvent, by producinga methyl ester of the fatty acid and then reacting the methyl ester withsucrose in DMF in the presence of a catalyst (e.g., potassiumcarbonate), for example, for 4-6 hours at 83-95° C., for example, using30 to 127 parts sucrose to 30 parts methyl ester of the fatty acid(e.g., methyl stearate), 2 parts potassium carbonate and 300 partssolvent; by a similar method, but using dimethyl sulfoxide (DMSO) as thesolvent, for example, as described in U.S. Pat. No. 3,480,616; or, asdescribed in U.S. Pat. No. 3,644,333, by mixing sucrose with methylfatty acid and sodium fatty acid and previously prepared sucrose ester,using potassium carbonate as a catalyst and water as a solvent; or, asdescribed in U.S. Pat. No. 3,714,144, where sodium, potassium or lithiumsoap of the fatty acid is reacted in a molten sugar solution for two totwenty minutes under vacuum at 170-190° C., and purified, for example,as described in U.S. Pat. No. 4,710,567, by adding aqueous salt solutionfollowed by three-phase separation. In one example, the sucrose fattyacid esters are prepared and purified as described in U.S. Pat. Nos.4,898,935, 4,996,309, 4,995,911, 5,011,922 and 5,017,697, by producingthe esters by chemical catalysis, such as with the solvent process,e.g., using a DMSO solvent and potassium carbonate catalyst, or aqueoussolution method, followed by extraction and purification of the sucrosefatty acid esters, e.g., by adjusting pH, precipitation, separation andneutralization and filtration.

In another example, the sucrose fatty acid esters can be produced, asdescribed in International Patent Application Publication No. WO2007/082149, by mixing and reacting sucrose and vinyl esters of thefatty acids which can produce sucrose fatty acid ester mixtures with amonoester content of at or about 90%, and/or an acid value of lessthan 1. Briefly, this process can be carried out by dissolving sucrosein a solvent (e.g., DMSO), at a reaction temperature of between at orabout 30° C. and at or about 60° C., such as between about 40° C. and60° C. (e.g., at 60° C.), and a catalyst added and the mixture stirred,such as for 30 minutes, followed by removal of undissolved catalyst bydecanting or filtration, followed by addition of vinyl fatty acid, andreaction, such as for at or about 15 minutes, with monitoring to measureamount of vinyl fatty acid ester, for example, until the amount of vinylfatty acid ester reaches no more than at or about 10%, by weight (w/w),of the starting amount. The amount of sucrose and vinyl ester can vary.In one example, the ratio of sucrose to vinyl ester is between at orabout 2:1 and at or about 8:1. In one example, the sucrose is added at aconcentration of at or about 400 nM and the vinyl ester added at aconcentration of at or about 100 nM. The catalyst can be catalyzed by abase, such as metal oxides, metal hydroxides and metal carbonates, suchas potassium hydroxide, sodium hydroxide, potassium carbonate, sodiumcarbonate and lithium carbonate, which can be added at a concentrationof between at or about 1.5 grams/L and at or about 6 g/L of reactionvolume. In one example, the vinyl ester is vinyl stearate and thecatalyst is potassium carbonate. The resulting mixture can thenpurified, such as by vacuum distillation and addition of sodium chlorideto effect emulsification and purification methods described inInternational Patent Application Publication No. WO 2007/082149.

(c) Stabilizers

The pre-spray emulsions provided herein can contain a stabilizer or astabilizing system. Stabilizers include any compound used to stabilizethe non-polar ingredients in the emulsions. The stabilizer orstabilizing system can aid in retaining one or more desirable propertiesof the compositions, for example the appearance, taste or odor. Thecompositions provided herein, including the pre-spray emulsions andspray-dried powders, containing non-polar ingredients and a stabilizeror stabilizing system can retain one or more desirable properties of thecomposition for a period of time after formulation, such as at or about1, 2, 3, 4, 5, 6, or 7 days, at or about 1, 2, 3, 4, 5, 6, 8, 12, 18,24, or 36 weeks, at or about 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, or 36months, or at or about 1, 2, 3, or 4 years. The stabilizers include, butare not limited to, carbonates and bicarbonates, acids, antioxidants,and any combination thereof. Typically the stabilizer or stabilizingsystem are food-approved, i.e., edible or ingestible, stabilizers, forexample, stabilizers that are safe and/or approved for humanconsumption.

Typically, when present, the total amount of stabilizers included in theprovided emulsions is less than 20% or about 20%, typically less than10% or about 10%, for example, less than 20%, 15%, 10%, 5%, 4.5%, 4%,3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%, by weight, of the emulsion.

(1) Bicarbonates and Carbonates

Exemplary of a stabilizer used in the provided pre-spray emulsions is abicarbonate or carbonate, for example, any edible or food-approvedbicarbonate or carbonate. Examples of suitable bicarbonates andcarbonates include sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, magnesium carbonate,zinc carbonate, and any combination thereof. In some examples, thecarbonate or bicarbonate is a carbonated beverage, such as a soda,flavored soda, carbonated water or carbonated juice. Alternatively, thebeverage can be carbonated by the addition of carbon dioxide. Selectionof suitable bicarbonates and carbonates for use in the provided beveragecompositions is within the skill of the skilled artisan.

(2) Ingestible Acids

The stabilizer used in the pre-spray emulsions can contain one or moreacids, for example, any compound added to the emulsion that can lowerthe pH of the emulsion. The acid can be, for example, an edible,ingestible or food-approved acid. Exemplary of suitable acids for use inthe provided pre-spray emulsions are citric acid, phosphoric acid,adipic acid, ascorbic acid, lactic acid, malic acid, fumaric acid,gluconic acid, succinic acid, tartaric acid, maleic acid, and anycombination thereof. In one example, the acid is citric acid.

(3) Antioxidants

The stabilizer used in the pre-spray emulsion can contain an ingestibleantioxidant, for example, a molecule that is capable of inhibiting theoxidation of other molecules. Antioxidants include molecules thatscavenge free radicals. Suitable antioxidants include those that areused as ingredients in dietary supplements. The antioxidant can be anatural antioxidant or a synthetic antioxidant.

Examples of antioxidants include, but are not limited to hormones,carotenoids, carotenoid terpenoids, non-carotenoid terpenoids,flavonoids, flavonoid polyphenolics (e.g., bioflavonoids), flavonols,flavones, phenols, polyphenols, esters of phenols, esters ofpolyphenols, nonflavonoid phenolics, isothiocyanates, vitamins andvitamin cofactors, such as vitamin A, vitamin C, vitamin E, vitamin Ephosphate and ubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10),ascorbic acid, citric acid, rosemary oil, minerals, such as mineralselenium and manganese, melatonin, α-carotene, β-carotene, lycopene,lutein, zeanthin, crypoxanthin, resveratrol, eugenol, quercetin,catechin, gossypol, hesperetin, curcumin, ferulic acid, thymol,hydroxytyrosol, tumeric, thyme, olive oil, lipoic acid, glutathione,glutamine, oxalic acid, tocopherol-derived compounds,di-alpha-tocopheryl phosphate, tocotrienols, butylated hydroxyanisole,butylated hydroxytoluene, ethylenediaminetetraacetic acid,tert-butylhydroquinone, acetic acid, pectin, tocotrienol, tocopherol,coenzyme Q10 (coQ10), zeaxanthin, astaxanthin, canthaxantin, saponins,limonoids, kaempferol, myricetin, isorhamnetin, proanthocyanidins,quercetin, rutin, luteolin, apigenin, tangeritin, hesperetin,naringenin, erodictyol, flavan-3-ols (e.g., anthocyanidins), green teaextract, gallocatechins, epicatechin and its gallate forms,epigallocatechin and its gallate forms, theaflavin and its gallateforms, thearubigins, isotlavone phytoestrogens, genistein, daidzein,glycitein, anythocyanins, cyaniding, delphinidin, malvidin, pelargonidinand peonidin. In one example, the antioxidant is vitamin C. In anotherexample, the antioxidant is a coenzyme Q-containing compound, such asubiquinone (ubidecarenone, coenzyme Q, coenzyme Q10).

(d) Polar Solvents

The pre-spray emulsions provided herein include one or more polarsolvents. Polar solvents are well known in the art. The polarity of asolvent generally indicates which compounds are soluble in the solvent,and with which other solvents/liquids the solvent is miscible. Generallyspeaking, polar compounds are more readily solubilized in water andother polar solvents than are non-polar ingredients. Polar solvents aremore likely to be miscible with water and other polar solvents andliquids.

The polarity of a solvent can be assessed by measuring a number ofdifferent parameters according to well-known methods (see, e.g.,Przybytek, “High Purity Solvent Guide,” Burdick and JacksonLaboratories, Inc., 1980), such as by determining a property of thesolvent, such as the dielectric constant, the dipole moment or thepolarity index. For example, polar solvents generally have highdielectric constants, typically dielectric constants greater than at orabout 15 (see, e.g., Lowery et al., “Mechanism and Theory in OrganicChemistry,” Harper Collins Publishers, 3rd ed., 1987, p. 177), such asat or about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 85, 90 orgreater than 90. For example, the dielectric constant of water is at orabout 80.10 at 20° C. Polar solvents generally have high polarityindices, typically greater than at or about 3 (see, e.g., Snyder,“Classification of the solvent properties of common liquids” (1974) J.Chromatog. A 92:223-230), such as at or about 3, 4, 5, 6, 7, 8 or 9 orgreater than 9. Polar solvents generally have large dipole moments,typically greater than at or about 1.4 Debye, such as at or about 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 3.0, 3.5, 4or greater than 4 Debye (see, e.g., “CRC Handbook of Chemistry andPhysics,” Lide, ed., 82nd edition, CRC Press, 2001, p. 15(14)-15(18)).Other methods of assessing solvent polarity are known in the art,including, but not limited to, the Kosower Z scale (Kosower, “Anintroduction to physical organic chemistry,” Wiley, 1969, p. 293), thedonor number and donor acceptor scale (Gutmann, “Solvent effects on thereactivities of organometallic compounds” (1976) Coord. Chem. Rev.18:225-255), and the Hildebrand solubility parameters (see, e.g.,Giddings et al., “High pressure gas chromatography of nonvolatilespecies. Compressed gas is used to cause migration of intractablesolutes” (1968) Science 162:67-73).

Polar solvents include polar protic solvents and polar aprotic solvents.A polar protic solvent (e.g., water, methanol, ethanol) contains ahydrogen atom attached to an electronegative atom, such that thehydrogen has a proton-like character and/or the bond between thehydrogen and electronegative atom is polarized. Polar aprotic solvents,on the other hand (e.g., acetone, acetonitrile), generally do notcontain positively polarized hydrogen atoms.

The polar solvents in the provided compositions typically are polarprotic solvents, including, but not limited to, water; alcohols, such asdihydric alcohols which contain two hydroxyl groups (for example,glycols, e.g., propylene glycol, ethylene glycol, tetraethylene glycol,triethylene glycol, trimethylene glycol), trihydric alcohols whichcontain three hydroxyl groups (e.g., glycerin, butane-1,2,3-triol,pentane-1,3,5-triol, 2-amino-2-hydroxymethyl-propane-1,3-diol),monohydric alcohols (e.g., methanol, ethanol, propanol, isopropanol,n-butanol and t-butanol) and other alcohols; and acids, such as aceticacid and formic acid. Other polar solvents include, but are not limitedto, acetone, acetonitrile, butyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, tetrahydrofuran andhexamethylphosphoric triamide. Typically, the polar solvent is water, oris an alcohol that typically contains two or more hydroxyl groups, suchas a trihydric or dihydric alcohol, such as, but not limited to,glycerol and propylene glycol. The polar solvents further include lowmolecular weight polyethylene glycols (PEGs), such as PEGs having amolecular weight not more than at or about 600 kDa, such as between orabout between 200 kDa and 600 kDa, typically not more than at or about400 kDa, for example, not more than 200 kDa.

In one example, the polar solvent has a dielectric constant greater thanat or about 15, and typically between at or about 20 and at or about 80,such as at or about 80.1. In another example, the polar solvent has apolarity index between at or about 3 and at or about 9. In anotherexample, the dipole moment of the polar solvent is between 1.5 and 3,and typically between at or about 1.8 and 2.8, such as 1.85 (fordielectric constants of solvents, see, for example, Landolt-Bornstein,New Series IV/17, “Static Dielectric Constants of Pure Liquids andBinary Liquid Mixtures,” Springer, 2008; and “CRC Handbook of Chemistryand Physics,” Lide, ed., 82nd edition, CRC Press, 2001; for dipolemoment of solvents, see, for example, “CRC Handbook of Chemistry andPhysics,” Lide, ed., 82nd edition, CRC Press, 2001; and for polarityindices of solvents, see, for example, Snyder, “Classification of thesolvent properties of common liquids,” J. Chromatography A, 92:223-230,1974).

When present, such as in the pre-spray emulsions, the amount of thepolar solvent typically is present in a high concentration, for example,the total amount of polar solvent as a percentage (%) by weight of theliquid concentrate (wt %) can be, e.g., between or between about 25% and70%, such as between or between about 35% and 65%, such as 35% to 40%,35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, 35% to 65%, 40% to 45%,40% to 50%, 40% to 55%, 40% to 60%, 40% to 65%, 45% to 50%, 45% to 55%,45% to 60%, 45% to 65%, 50% to 55%, 50% to 60%, 50% to 65%, 55% to 60%,55% to 65%, and 60% to 65% polar solvent, by weight, of the pre-sprayemulsion. Exemplary concentrations of the polar solvent in the pre-sprayemulsions are at or about 45%, 48%, 50%, 52%, 55%, 56%, 57%, 58%, 60%,62%, 65%, 68%, and 70% (w/w) of the pre-spray emulsion.

In the provided methods for making the pre-spray emulsions, the polarsolvent is added to the water phase. In one example, the polar solventis water, e.g., purified water, such as water that is purified prior toadding it to the concentrate formula, for example, by charcoal filter,ion exchange, reverse osmosis, UV sterilization and/or filtering using afilter, for example, a 50-100 micron filter. Typically, when a filter isused, it is an end point of use filter, which filters the water beforeit reaches the tank in the provided process. Alternatively, previouslyfiltered water can be added to the concentrates.

(e) Binders

As discussed above, the provided pre-spray emulsions contain a binderfor forming a powder when dried. The binder is any ingestible materialthat capable of adhering other materials together during drying, such asspray-drying and/or lyophilization. Exemplary binders include, but arenot limited to, polysaccharides, polyols, starches, and gums. Forexample, the binder can be, maltodextrin, lactose, sucrose,maltodextrin, starch, polyethylene glycol, gums, hypromellose,methylcellulose, macrocrystalline cellulose, polyethylene glycol,sorbitol, other sugars, and pectin. An exemplary binder is maltodextrin,a moderately sweet polysaccharide produced from starch as a creamy whitehygroscopic powder. Maltodextrin is easily digestible, being absorbed asrapidly as glucose. Maltodextrin can be derived from any starch. In theU.S., this starch is usually corn or potato, whereas elsewhere (e.g.,Europe), it is commonly wheat.

When present, the amount of binder, such as maltodextrin, typically ispresent in an amount of between or between about 5% and 30% binder, suchas between or between about 5% and 7%, 5% and 10%, 5% and 12%, 5% and15%, 5% and 17%, 5% and 20%, 7% and 10%, 7% and 12%, 7% and 15%, 7% and17%, 7% and 20%, 7% and 28%, 10% and 12%, 10% and 15%, 10% and 17%, 10%and 20%, 15% and 17%, 15% and 20%, and 17% and 20%, 15%-28%, 15%-25%, byweight of the emulsion.

As described herein, the sugar fatty acid esters, such as the SFAE(s),are included, not only for the surfactant properties, but also inaddition to the binder or in place of some or all of the binder.Typically, when a binder, e.g., maltodextrin, is present, the totalamount of binder, e.g., maltodextrin, and surfactant, for example, sugarfatty acid ester, e.g., sucrose fatty acid ester, is between about 5%and 40% binder and sugar fatty acid ester, such as between or betweenabout 5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and 30%, 5% and35%, 5% and 40%, 10% and 15%, 10% and 20%, 10% and 25%, 10% and 30%, 10%and 35%, 10% and 40%, 15% and 20%, 15% and 25%, 15% and 30%, 15% and35%, 15% and 40%, 20% and 25%, 20% and 30%, 20% and 35%, 20% and 40%,25% and 30%, 25% and 35%, 25% and 40%, 30% and 35%, 30% and 40%, and 35%and 40% total binder and surfactant, e.g., sucrose fatty acid ester, byweight of the emulsion.

(f) Co-Surfactants (Emulsifiers)

The pre-spray emulsions can further contain one or more co-surfactants(emulsifiers). For example, a co-surfactant can be included to improveemulsification of the non-polar ingredients and/or the stability of theemulsion, for example, by preventing or slowing oxidation of thenon-polar ingredients. Exemplary of a co-surfactant that can be used inthe provided concentrates is a phospholipid, for example,phosphatidylcholine. Other exemplary co-surfactants include non-ionicsurfactants, such as sugar-derived surfactants, including fatty acidesters of sugars and sugar derivatives, and PEG-derived surfactants,such as PEG derivatives of sterols, PEG derivatives of fat-solublevitamins and PEG-sorbitan fatty acid esters. Other exemplaryco-surfactants are fish collagen, for example, the fish collagen sold byNorland Products Inc. (Cranbury Township, N.J.) and saponin, such assaponin from quillaja bark, including the saponin from quillaja barksold by Desert King International (San Diego, Calif.) and Sigma Aldrich(St. Louis, Mo.).

When present, the amount of the co-surfactant typically is present in aconcentration less than or less than about 10%, typically less than orless than about 5%, for example, the total amount of co-surfactant as apercentage (%), by weight, of the emulsion (wt %) can be, e.g., lessthan or less than about 10%, such as less than or about 5%, 4.5%, 4%,3.5%, 3.15%, 3%, 2.5%, 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, 0.5%, 0.25%,0.15% or less, by weight, of the emulsion.

(1) Phospholipids

Exemplary of the co-surfactants that can be used in the providedemulsions are phospholipids. Phospholipids are amphipathic lipid-likemolecules, typically containing a hydrophobic portion at one end of themolecule and a hydrophilic portion at the other end of the molecule. Anumber of phospholipids can be used as co-surfactants in the providedcompositions, for example, lecithin, including phosphatidylcholine (PC),phosphatidylethanolamine (PE), distearoylphosphatidylcholine (DSPC),phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid(PA), phosphatidylinositol (PI), sphingomyelin (SPM) or a combinationthereof. Typically, the phospholipid is phosphatidylcholine (PC), whichsometimes is referred to by the general name “lecithin.” Exemplary ofthe phospholipids that can be used as co-surfactants in the providedcompositions are the phospholipids sold by Lipoid, LLC (Newark, N.J.),for example, Purified Egg Lecithins, Purified Soybean Lecithins,Hydrogenated Egg and Soybean Lecithins, Egg Phospholipids, SoybeanPhospholipids, Hydrogenated Egg and Soybean Phospholipids, SyntheticPhospholipids, PEG-ylated Phospholipids and phospholipid blends.Exemplary of the phosphatidylcholine that can be used as a co-surfactantin the provided compositions is the phosphatidylcholine composition soldby Lipoid, LLC, under the name Lipoid S100, which is derived from soyextract and contains greater than or greater than about 95%phosphatidylcholine.

(2) PEG-Derived Surfactants

Exemplary PEG-derived surfactants include, but are not limited to, PEGderivatives of sterols, e.g., a cholesterol or a sitosterol (including,for example, any of the PEG derivatives disclosed in U.S. Pat. No.6,632,443); PEG derivatives of fat-soluble vitamins, for example, someforms of vitamin A (e.g., retinol) or vitamin D (e.g., vitamin D1-D5);and PEG-sorbitan fatty acid esters, such as polysorbates, includingpolyoxyethylene (20) sorbitan monooleate (also called polysorbate 80)and analogs (e.g., homologs) of polysorbate 80, such as, for example,polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate40 (polyoxyethylene (20) sorbitan monopalmitate) and polysorbate 60(polyoxyethylene (20) sorbitan monostearate); and stearic acidderivatives, including, for example, polyethylene glycol 400 distearate(PEG 400 DS), such as the PEG 400 DS sold by Stepan Lipid Nutrition(Maywood, N.J.).

(g) Emulsion Stabilizers (Co-Emulsifiers)

The pre-spray emulsions can further contain one or more emulsionstabilizers (co-emulsifiers), which can be used to stabilize theemulsions containing the pre-emulsion concentrates. For example, theemulsion stabilizer can increase the viscosity of the concentrate. Oneor more emulsion stabilizers can be added, for example, duringformulation after evaluation of an initial emulsion, particularly if theoil and water phases of the initial emulsion appear to be separating.Addition of the emulsion stabilizer can prevent separation of the oiland water phases.

Exemplary of an emulsion stabilizer that can be included in the providedemulsions is a composition containing a blend of gums, for example, gumsused as emulsifying agents, for example, a blend containing one or moreof xanthan gum, guar gum and sodium alginate. Exemplary of such anemulsion stabilizer includes the emulsion stabilizer sold under thebrand name SALADIZER®, available from TIC Gums, Inc. (Belcamp, Md.).Other gums can be included in the emulsion stabilizer, for example, gumacacia, ester gums and sugar beet pectin. Exemplary emulsion stabilizersinclude modified food starches. These include the modified gum acaciasold under the name Tic Pretested® Ticamulsion® A-2010 Powder, availablefrom TIC Gums, Inc. (Belcamp, Md.). Other exemplary emulsion stabilizerscontaining an ester gum are, for example, the emulsion stabilizer soldunder the name Tic Pretested® Ester Gum 8BG, available from TIC Gums,Inc. (Belcamp, Md.) or Ester Gum 8BG, available from Hercules/Pinova(Brunswick, Ga.). Others sold by Ingredion, Inc. (Westchester, Ill.)under the trademarks CAPSUL®, FIRMTEX®, THERMFLO®, THERMTEX®, andTEXTRA® and others, can be included in the compositions provided herein.Other blends of similar gums can also be used as emulsion stabilizers.

Also exemplary of an emulsion stabilizer that also can serve as a binderis whey protein. Whey protein is a protein contained in the milk serum(whey) obtained by removing casein and other components from milk, andcomprises lactoalbumin, lactoglobulin, and lactoferrin as maincomponents. Whey protein is known to have such functions as a staminaimprover, a fatigue reliever, and an immunity enhancer. In addition, itis used as a protein supplement material in athletic nutrient foods anddiet foods. Whey proteins are often used in food emulsion systemsbecause of their ability to stabilize oil-in-water (O/W) emulsions. Anexemplary whey protein is the whey protein isolate sold by MarquezBrothers International (Hanford, Calif.).

Another exemplary emulsion stabilizer is green tea extract, which ishigh in epigallocatechin gallate (EGCG) and epicatechin gallate (ECG).Green tea extract is known to have high antioxidant activity and theability to provide stability to emulsions. An exemplary green teaextract that can be used in the pre-spray a green tea extract thatcontains 40% EGCG, such as one sold by Guilin Layn Natural Ingredients,Corp. (Guilin, China).

When present, the emulsion stabilizer is typically present at aconcentration of less than 10%, such as less than or less than about10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%, by weight, of the emulsion.For example, the emulsion stabilizer can be added to the water phase ata concentration of between 0.01% or about 0.01% and 10% or about 10%,for example, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 1.5%, 2%, 2.5%,3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9% or 10% w/w of the emulsion.

(h) pH Adjusters

One or more pH adjusters can be added to the emulsions at an appropriateconcentration to achieve a desired pH. One or more of a plurality of pHadjusting agents can be used. The pH adjusting agent typically is safefor human consumption, for example, GRAS certified. The pH adjuster canbe citric acid. An exemplary pH adjuster includes the citric acid soldby Mitsubishi Chemical (Dublin, Ohio). Another exemplary pH adjuster isphosphoric acid, such as Food Grade 80% Phosphoric Acid, sold by Univar.

b. Powder Compositions Containing Non-Polar Ingredients

The pre-spray emulsions containing the pre-emulsion concentratesprovided herein are dried, such as by evaporation of the water, spraydrying or lyophilization or other drying method to produce the powdersThe water-soluble powders are prepared b removing all of the polarsolvent, such as water, from the pre-spray emulsion, to form afree-flowing powder that does not contain any, or only minimal amounts,of polar solvent. The resulting powders contain high concentrations ofnon-polar ingredients and display advantageous properties. They arefree-flowing, i.e., not sticky, powder rather than a sludge-like, oilysubstance. They contain high concentration of non-polar ingredients. Thepowders provided herein typically contain the same ingredients as thecorresponding pre-spray emulsion, with the exception of the polarsolvent, e.g., water, that is removed during the drying process. Removalof the polar solvent, e.g., water, from the pre-spray emulsion resultsin an increased concentration (i.e., wt %) of each ingredient in thepowder compared to the corresponding emulsion. For example, thepre-spray emulsions provided herein contain between or between about 5wt % and 30 wt % non-polar ingredient(s) and produce powders thatcontain between or between about 10 wt % and 60 wt %, such as greaterthan 30% non-polar ingredient(s) after spray drying. The providedpowders (and methods for making the powders) can be used to formulateany non-polar ingredient in a water-soluble powder, including thenon-polar ingredients (e.g., non-polar ingredients that are or containnon-polar compounds) described herein and other known non-polaringredients.

Methods of producing powders from liquid compositions are well known tothe skilled artisan. Exemplary processes for producing powders include,but are not limited to spray drying, freeze drying and absorptionplating. The methods for forming the powders include spray drying. Spraydrying processes and spray drying equipment are described generally inPerry's Chemical Engineers' Handbook, pp. 20-57 (Sixth Edition 1984).More details on spray drying processes and equipment are reviewed byMarshall (1954) “Atomization and Spray-Drying,” Chem. Eng. Prog. Monogr.50: Series 2 and Masters, “Spray Drying Handbook” (Fourth Edition 1985).Methods for spray drying are well known (see, e.g. U.S. Pat. Nos.5,430,021 and 6,534,085 and U.S. Publication No. US 2007/0184117). Ingeneral, spray drying is used to dry a heated liquid by passing itthrough hot gas. One or more spray nozzles is used to atomize the liquidin a cooling tower or chamber. As the material is atomized (sprayed),the surface tension causes a uniform spherical particle to form, whichis passed through the cooling chamber and hardens into a solid intactsphere. The spray dried particles can be between at or about 0.5 micronsand at or about 100 microns, and typically are less than at or about 10microns, typically less than at or about 5 microns, and typically lessthan at or about, or at or about, 1 micron.

The powder compositions provided herein can be made from any emulsioncontaining non-polar ingredients, a sugar fatty acid ester, and apolyalkylene glycol derivative of vitamin E, such as the pre-sprayemulsions provided herein. As noted, for purposes herein the PEGderivative of vitamin E is a high dimer-containing composition asdescribed herein.

i. Formulating the Powder Compositions

The powder compositions provided herein are water-soluble and have highconcentrations of non-polar ingredients, for example, at least 10%, 20%,30%, 40%, 50%, 55% and more, such as 60%, and are stable andfree-flowing, i.e., not sticky, sludgy or oily. The powders also containa sugar fatty acid ester(s), e.g., a sucrose fatty acid ester, that alsoacts as a binder and/or in combination with a binder, that does notcontribute to the oil load of the powder, resulting in a powder with thehigh concentrations of non-polar ingredients. The sugar fatty acidesters, such as sucrose fatty acid esters, are present in thewater-soluble powders in place of or in combination with a binder, andresult in powders that are water-soluble, free-flowing, i.e., notsticky, and contain high concentrations of non-polar ingredients.

The pre-emulsion concentrates and pre-spray emulsions provided hereinare formulated such that drying the resulting emulsion, e.g., spraydrying, yields a powder composition that contains high concentrations ofnon-polar ingredient, yet is free-flowing, i.e., not sticky, andwater-soluble. A number of parameters of the concentrates and emulsions,including ingredients, their relative concentrations, and methods formaking the concentrates and emulsions, affect the ability of emulsion toform a free-flowing, i.e., not sticky, powder when a high concentrationof non-polar ingredient is present. By extension, these parameters ofthe concentrates and emulsions also affect the advantageous propertiesof the powders, for example, the solubility of the powder, for example,in an aqueous solution.

Thus, the pre-spray emulsions are formulated such that after drying,e.g., spray drying, the resulting powder compositions display one ormore advantageous properties, for example, the powder is free-flowing,i.e., not sticky, and/or the powder is water-soluble. In one example,the advantageous property is the ability of the provided emulsions toyield powder compositions that have no or only a minimal amount of polarsolvent, e.g., water and are free-flowing, i.e., not sticky, afterdrying, for example, spray drying. In another example, the advantageousproperty relates to the ability of the pre-spray emulsions to be dried,e.g., spray dried, to form a powder that contains a high concentrationof non-polar ingredients and is water-soluble.

ii. Ingredients and Concentration Ranges

Each of the provided powder compositions contains a pre-spray emulsionthat has been dried, for example, spray dried, to remove all or almostall of the polar solvent, e.g., water. The pre-spray emulsions, andthus, the powder compositions provided herein, contain the pre-emulsionconcentrates provided herein that contain non-polar ingredients and apolyalkylene glycol surfactant, e.g., TPGS. In some examples, thepre-emulsion concentrate contains a preservative, e.g., benzyl alcohol.The pre-spray emulsions, and thus, the powder compositions providedherein additionally contain a surfactant, such as a sugar fatty acidester, e.g., sucrose fatty acid ester, in place of or in combinationwith a binder, e.g., maltodextrin, and additional ingredients,including, but not limited to, stabilizers, e.g., bicarbonates orcarbonates, acids, and/or antioxidants, co-surfactants (emulsifiers),e.g., phospholipids and/or PEG-derived surfactants, emulsion stabilizers(co-emulsifiers), pH adjusters, e.g., citric acid, and any of theingredients provided herein in Section B.2.b., with the exception ofpolar solvents, e.g., water.

Each of the provided powder compositions contains a non-polaringredient, including, but not limited to, the exemplary non-polaringredients described herein above. Typically, the non-polar ingredientis or contains one or more non-polar compounds. The powder compositionsprovided herein can contain one non-polar ingredient or more than onenon-polar ingredient, such as two, three, four, five, six, seven, eight,or more non-polar ingredients. The powder compositions provided hereincan contain high amounts (i.e., concentrations) of non-polaringredients, such as up to at or about 60 wt % non-polar ingredients.

The powders provided herein contain high amounts of non-polaringredients, e.g., non-polar ingredients that are or contain non-polarcompounds, for example, between or between about 10 wt % and 60 wt %non-polar ingredient, such as between or between about 10% and 15%, 10%and 20%, 10% and 25%, 10% and 30%, 10% and 35%, 10% and 40%, 10% and45%, 10% and 50%, 10% and 55%, 10% and 60%, 15% and 20%, 15% and 25%,15% and 30%, 15% and 35%, 15% and 40%, 15% and 45%, 15% and 50%, 15% and55%, 15% and 60%, 20% and 25%, 20% and 30%, 20% and 35%, 20% and 40%,20% and 45%, 20% and 50%, 20% and 55%, 20% and 60%, 25% and 30%, 25% and35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and 55%, 25% and 60%,30% and 35%, 30% and 40%, 30% and 45%, 30% and 50%, 30% and 55%, 30% and60%, 35% and 40%, 35% and 45%, 35% and 50%, 35% and 55%, 35% and 60%,40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%, 45% and 50%, 45% and55%, 45% and 60%, 50% and 55%, 50% and 60%, and 55% and 60%, by weightof the powder. The powder compositions that contain high amounts ofnon-polar ingredient and a sugar fatty acid ester surfactant in place ofor in combination with a binder, e.g., maltodextrin, exhibit desirableproperties, for example, the powder is a free-flowing, i.e., not sticky,powder that is water-soluble.

Each of the provided powder compositions contain a pre-emulsionconcentrate that contains at least one surfactant that is a polyethyleneglycol derivative of vitamin E, for example, TPGS, TPGS analogs, TPGShomologs and TPGS derivatives described herein. The surfactant typicallyhas an HLB value of between 12 or about 12 and 20 or about 20, forexample, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about 12, about 13,about 14, about 15, about 16, about 17, about 18, about 19 or about 20,typically between at or about 12 and at or about 14. For example, TPGS,such as the TPGS described herein, has an HLB value of about 13.

The polyethylene glycol derivative of vitamin E, e.g., TPGS, istypically present in an amount as a percentage (%) by weight of thepowder compositions (wt %), e.g., from at or about 0.1% to at or about20%, such as 0.1% to 0.5%, 0.1% to 1%, 0.1% to 2%, 0.1% to 5%, 0.1% to7%, 0.1% to 10%, 0.1% to 12%, 0.1% to 15%, 0.1% to 20%, 0.5% to 1%, 0.5%to 2%, 0.5% to 5%, 0.5% to 7%, 0.5% to 10%, 0.5% to 12%, 0.5% to 15%,0.5% to 20%, 1% to 2%, 1% to 5%, 1% to 7%, 1% to 10%, 1% to 12%, 1% to15%, 1% to 20%, 2% to 5%, 2% to 7%, 2% to 10%, 2% to 12%, 2% to 15%, 2%to 20%, 5% to 7%, 5% to 10%, 5% to 12%, 5% to 15%, 5% to 20%, 7% to 10%,7% to 12%, 7% to 15%, 7% to 20%, 10% to 12%, 10% to 15%, 10% to 20%, 12%to 15%, 12% to 20%, and 15% to 20%, by weight, of the powdercompositions. Exemplary concentrations of the polyethylene glycolderivative of vitamin E, e.g., TPGS, in the powder compositions are ator about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 7%, 10%, 12%, 15%,17% and 20% (wt %) of the powder compositions.

The powder compositions contain a sugar fatty acid ester surfactant inplace of or in combination with a binder, e.g., maltodextrin. Typically,the sugar fatty acid ester is a sucrose fatty acid ester. Thesurfactant, e.g., sucrose fatty acid ester, does not contribute to theoil load of the composition, thus allowing the addition of highconcentrations of non-polar ingredients and formation of a free-flowing,i.e., not sticky, powder. In one example, the powder contains a sugarfatty acid ester, e.g., sucrose fatty acid ester, in place of a binder,e.g., maltodextrin. In another example, the powder contains a sugarfatty acid ester, e.g., sucrose fatty acid ester, in combination with abinder, e.g., maltodextrin.

The powder compositions provided herein contain a surfactant, such as asugar fatty acid ester, e.g., sucrose fatty acid ester, where the totalamount of surfactant, e.g., sucrose fatty acid ester, is typicallypresent in an amount as a percentage (%) by weight of the powdercompositions (wt %), e.g., from at or about 5 wt % to at or about 30 wt%, such as between or between about 5% and 7%, 5% and 10%, 5% and 12%,5% and 15%, 5% and 17%, 5% and 20%, 5% and 25%, 5% and 30%, 7% and 10%,7% and 12%, 7% and 15%, 7% and 17%, 7% and 20%, 7% and 25%, 7% and 30%,10% and 12%, 10% and 15%, 10% and 17%, 10% and 20%, 10% and 25%, 10% and30%, 12% and 15%, 12% and 17%, 12% and 20%, 12% and 25%, 12% and 30%,15% and 17%, 15% and 20%, 15% and 25%, 15% and 30%, 17% and 20%, 17% and25%, 17% and 30%, 20% and 25%, 20% and 30%, and 25% and 30% sugar fattyacid ester, e.g., sucrose fatty acid ester, by weight of the soft gelcompositions. Exemplary concentrations of the total amount of sugarfatty acid ester, e.g., sucrose fatty acid ester in the powdercompositions are at or about 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25% and30% (wt %) of the powder compositions.

The powder compositions provided herein can contain a binder. Exemplarybinders include, e.g., maltodextrin. Typically, when a binder, e.g.,maltodextrin, is present in the powder composition, the total amount ofbinder, e.g., maltodextrin, and surfactant, such as a sugar fatty acidester, e.g., sucrose fatty acid ester, is typically present in a totalamount as a percentage (%) by weight of the powder compositions (wt %),e.g., from at or about 5 wt % to at or about 60 wt %, such as between orbetween about 5% and 10%, 5% and 15%, 5% and 20%, 5% and 25%, 5% and30%, 5% and 35%, 5% and 40%, 5% and 45%, 5% and 50%, 5% and 55%, 5% and60%, 10% and 15%, 10% and 20%, 10% and 25%, 10% and 30%, 10% and 35%,10% and 40%, 10% and 45%, 10% and 50%, 10% and 55%, 10% and 60%, 15% and20%, 15% and 25%, 15% and 30%, 15% and 35%, 15% and 40%, 15% and 45%,15% and 50%, 15% and 55%, 15% and 60%, 20% and 25%, 20% and 30%, 20% and35%, 20% and 40%, 20% and 45%, 20% and 50%, 20% and 55%, 20% and 60%,25% and 30%, 25% and 35%, 25% and 40%, 25% and 45%, 25% and 50%, 25% and55%, 25% and 60%, 30% and 35%, 30% and 40%, 30% and 45%, 30% and 50%,30% and 55%, 30% and 60%, 35% and 40%, 35% and 45%, 35% and 50%, 35% and55%, 35% and 60%, 40% and 45%, 40% and 50%, 40% and 55%, 40% and 60%,45% and 50%, 45% and 55%, 45% and 60%, 50% and 55%, 50% and 60%, and 55%and 60% total amount of binder, e.g., maltodextrin, and sugar fatty acidester, e.g., sucrose fatty acid ester, by weight of the powdercompositions. Exemplary concentrations of the total amount of binder,e.g., maltodextrin, and sugar fatty acid ester, e.g., sucrose fatty acidester in the powder compositions are at or about 5%, 7%, 10%, 12%, 15%,17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60% (wt %) of thepowder compositions.

Typically, when the powder compositions provided herein contain amixture of surfactant, such as a sugar fatty acid ester, e.g., sucrosefatty acid ester, and binder, e.g., maltodextrin, such as a mixture ofsurfactant, e.g., sucrose fatty acid ester, and binder, e.g., that ispresent in an amount between or about between 5 wt % and 60 wt %, themixture contains at least or about at least 5% sugar fatty acid ester,e.g., sucrose fatty acid ester, e.g., at least or about at least 5%, 7%,10%, 15%, 20%, or more, sugar fatty acid ester, e.g., sucrose fatty acidester, by weight of the powder.

E. Exemplary Methods for Preparing Products Containing HighDimer-Containing Water-Soluble Vitamin E Derivative Mixtures

Methods for preparing products containing the high dimer-containingwater-soluble vitamin E derivative mixtures, e.g., TPGS compositions,for example, products for human consumption, such as food and beverageproducts, in particular aqueous food and beverage products, are providedherein. For example, methods for preparing the concentrates providedherein are described. Equipment for use in the methods and general stepsof the methods are described below. The methods include bench-topmanufacturing processes, which are used to make small quantities of theproducts. The methods also include scaled-up manufacturing processes,which are used to make larger batches of the products. Any of thebench-top processes can be scaled up to perform the methods using thescaled-up processes. Any of the provided products can be made usingeither scaled-up or bench-top processes. The concentrates and liquiddilution compositions provided herein can be made following the methodsprovided in U.S. Pat. No. 8,282,977 and U.S. Pub. Nos. 2009-0297491 and2012-0016026.

1. Equipment Employed in the Methods

Equipment used in various steps of the provided methods for making theproducts can include, for example, vessels, such as tanks, for mixingthe water and oil phases and the product; scales; mixers, for examplestandard mixers and homogenizers; heating and cooling apparatuses, suchas water-jacketed tanks, hot plates, water baths and chillers (coolers),including recirculating coolers; transfer apparatuses, for example,transfer devices, such as, pumps, hoses and sanitary fittings; ballvalves; purifiers, for example, filters, such as carbon filters, ionexchange equipment, reverse osmosis equipment, end-point filters and endproduct filters; evaluation devices, for example, pH and temperaturemeters; and other equipment. The choice of equipment depends on aplurality of factors, including batch size and the manufacturingprocess.

a. Scales

One or more scales can be used to measure the amount of the ingredientsbefore adding them to the appropriate vessel. Alternatively, theingredients can be weighed in the vessel, for example, in a tank on topof a scale.

Any of a plurality of well-known, commercially sold scales can be usedto weigh the ingredients. The choice of scale(s) can depend on a numberof factors, including the mass of the product being made (e.g., thebatch size) and the ingredient being weighed. In one example, multiplescales are used to weigh the various ingredients of the products. Ingeneral, relatively larger capacity (i.e., weight) scale(s) are used inmaking larger batches of the products while relatively smaller capacityscale(s) are used in making smaller batches.

Exemplary of the scales used to weigh the ingredients using the providedmethods are a Toledo Scale (Model GD13x/USA); a Sartorius BasicAnalytical Scale (Model BA110S), which is a basic series analyticalscale with a 110 g capacity and a resolution of 0.1 mg; and an OHAUSScale (Model CS2000), which is a compact portable digital scale having a2000 g capacity and a resolution of 1 g.

b. Purifiers

Purifiers, such as filters, are used in the provided methods to removeimpurities from the ingredients prior to their addition to and/or fromthe product or to and/or from a phase of the product. For example, thewater added to the water phase typically is purified water. In oneexample, one or more purifiers, for example, carbon filters, ionexchange purifiers, reverse osmosis purifiers, and/or end point filterscan be used to filter water, for example, city water, prior to itsaddition to the water phase. For example, the water can be filtered toremove impurities, such as sediment, from the water.

Purifiers that can be used with the provided methods include filters,for example, 100 micron filters and carbon filters, which are filtersthat use activated carbon to remove impurities by chemical adsorption.Carbon filtering typically is used for water purification and isparticularly effective at filtering out chlorine, sediment, volatileorganic compounds and other impurities. Typically, the particles removedby carbon filters are between about 0.5 microns and about 50 microns.Other filters are well known and can be used with the provided methods.

The purifiers also include reverse osmosis purifiers, which usemechanical pressure to purify liquids, for example, water. In oneexample, the pressure forces the water through a semi-permeable membraneto remove impurities.

The purifiers also include exchange purifiers, for example, an ionexchange purifier. The ion exchange purifier can use a resin bed, suchas a zeolite resin bed, to replace salts, such as cations, e.g.,magnesium and calcium, with other cations, such as sodium and potassiumcations. Such purifiers can be purchased, for example, from Aqua-PureFilters (Clarkston, Mich.).

In one example, the purifier is an end product filter (e.g., a 100micron filter; Product No. BPEM 100-5GP; FSI, Michigan City, Ind.). Thisfilter is used to filter any impurities out of the final product (e.g.,the final pre-emulsion composition). Other filters also are known andcan be used with the provided methods.

c. Vessels

One or more, typically two or more, vessels, can be used in the methodsto contain the ingredients of the provided products, for example, duringmixing and/or heating or cooling. The vessels can be tanks, for example,water-jacketed tanks; pots; and/or beakers, for example, Pyrex® beakers.Separate vessels (e.g., an oil phase tank and a water phase tank) can beused for mixing and heating the ingredients of the oil phase and thewater phase prior to combining the two phases. In some examples, anadditional vessel, for example, a holding and/or packaging tank, can beused for holding and/or packaging the products and/or foraddition/mixing of additional ingredients to the products.

A number of vessels are available for mixing ingredients. Typically, thevessels are cleaned, for example, rinsed, soaped and/or sanitized,according to known procedures prior to use and between uses, such aswith the cleaning procedures described below.

In the bench-top process, the vessel can be a container, for example, abench-top container, such as a flask, beaker (e.g., a Pyrex® beaker),vial, measuring container, bottle and/or other bench-top container.

In the scaled-up manufacturing process, the vessels can be tanks, forexample, water phase tanks, oil phase tanks and holding/packaging tanks.Typically, the tanks are equipped with one or more mixers, for example,a standard mixer and/or homogenizer, which are used to mix theingredients that are added to the tank. In one example, the tank isfurther equipped with a heating and/or cooling device. For example, thetank can be a water-jacketed tank. The temperature of the water-jacketedtank is controlled through the water jacket, for example, to heat thecontents, such as during mixing.

Exemplary of the tanks that can be used with the provided methods arewater-jacketed tanks, for example, the Overly 550 gallon water-jacketedtank (Model 10576501G), which has a 550 gallon capacity and typically isused as a water phase tank, the Schweitzer's 450 gallon tank (Model#5214-C), which has a 450 gallon capacity and typically is used as anoil phase tank and the Royal 190 gallon water-jacketed tank (Model9977-5), which has a 190 gallon capacity and can be used as a water oroil phase tank when mixing smaller volumes. Other tanks are well knownand can be used with the provided methods for mixing the products, forexample, the phases of the product.

d. Mixers

Mixers are used in the methods to blend, mix and/or emulsify theproducts and ingredients, mixtures and phases of the products. In someexamples, the mixers can be used to keep the ingredients and/or mixturecirculating to maintain temperature, viscosity and/or other parametersof the mixture. Suitable mixers include, but are not limited to,standard mixers, for example, those that can be used to mix ingredientsand maintain a homogeneous mixture, such as while heating a mixture ofingredients. Exemplary of the standard mixers are LIGHTNIN® mixers(LIGHTNIN, Rochester, N.Y.), for example, Model Numbers XJC117 and ND-2.In one example, the LIGHTNIN® mixers are fixed-mount, gear drivehigh-flow mixers, for use with closed tanks. Another example of astandard mixer is a mixer sold by IKA®, for example, overhead IKA®mixers. Exemplary IKA® mixers include Model Nos. RW-14 Basic and RE-16S,which are laboratory stirrers that can be used to mix ingredients. Insome examples, the mixer can be attached to the vessel, e.g., the tank,such as by mounting or clamping onto the tank, such as at the top of thetank. In other examples, the mixer can be placed in the vessel formixing.

The mixer can be a homogenizer which can be used, for example, toemulsify mixtures, i.e., form an emulsion. The homogenizer can be usedto mix phases of the compositions, e.g., oil and water phases, aftercombining the phases, in order to form an emulsion. The homogenizerprovides high-shear dispersion of solids and emulsification ofimmiscible liquids at high shear rates. Suitable homogenizers include,but are not limited to, high-shear homogenizers, for example, reversiblehomogenizers sold by Arde Barinco, Inc. (Norwood, N.J.). Exemplary ArdeBarinco, Inc. reversible homogenizers are Model CJ-50 (a 3600 rpm mixerhaving a 6-inch rotor diameter, tip speed of 5575 ft/minute, emersiondepth of 33 inches, and six separate openings at the bottom and top,which concentrate the liquid into six chambers, reducing the surfacevolume and creating a shear effect); and Model CJ-4E (a 10,000 rpm mixerwith fan-cooled motor, optimized for 1 to 5 gallon batch sizes, having a1.875 inch rotor diameter, tip speed of 4920 rpm, and immersion depth of16 inches). The homogenizers further include other homogenizers, forexample, other reversible homogenizers sold by Arde Barinco, Inc.

In one example, the homogenizer is attached to the top of the vessel,for example, the tank, for example, by clamps or by channel locks and anelectrical hoist. In another example, the homogenizer is placed in thevessel. The Arde Barinco reversible homogenizers contain axial flowimpellers, which create two distinct mixing actions, depending ondirection. Downward “vortex flow” pulls solids from the top and bottomof the mixture, while upward “umbrella flow” controls mixing at thehighest shear and recirculation rates without splashing or incorporatingair. The reversible homogenizers typically are equipped with anadjustable baffle plate, which can be adjusted to control the type ofmixing, for example at different times during mixing, e.g., duringemulsification.

A number of other mixers are well known and can be used with theprovided methods. Exemplary of suitable mixers that can be used with theprovided methods are homogenizers, inline mixers, ribbon mixers, plowmixers, paddle mixers, Forberg® mixers, conveyors, bag dumps andcompactors, V-blenders, blade mixers, double cone mixers, continuousmixers, speedflow mixers, batch mixers, double ribbon blenders, paddleand ribbon mixers with choppers, plow blenders, turbulent mixers,fluidizing Forberg-type mixers, air mixers, active mixers, passivemixers, top-entry mixers, side-entry mixers, static mixers, fixed-entrymixers, portable mixers (e.g., direct and gear drive), sanitary mixers,drum mixers, bulk container (IBC) mixers, lab stirrers, variable speedmixers, dough mixer, vertical mixer, spiral mixer, twin arm mixer, forkmixer, double spiral mixer, all agitators, agitator mixers, Banbury®mixers, rubber mixers, Blondheim mixers, churn mixers, conical mixers,continuous mixers, disperser mixers, pan mixers, emulsifier mixers,Hobart® mixers, liquifier mixers, Littleford mixers, meat mixers, plowmixers, Mix-Muller® Mixers, vertical screw mixers (e.g., Nauta mixers),Oakes mixers, planetary mixers, pony mixers, pug mixers, Ross mixers,rotary mixers, Sigma mixers, single arm mixers, tote bin mixers, tumblemixers, vacuum mixers, Turbolizer mixers, twin shell mixers, V-typemixers, zigzag mixers, side-arm mixers, hand-held mixers, stir rods,stir bars, magnetic mixers, overhead mixers (e.g., mechanical and/orelectric overhead mixers), and any mixer known to those of skill in theart.

e. Heating/Cooling Apparatuses

Equipment that can be used in the methods includes heating and coolingapparatuses. The heating and cooling apparatuses can be used to controlthe temperature of the ingredients and combinations thereof, such aswhile generating the products.

Heating apparatuses that can be used in the provided methods are thosethat are capable of heating the mixture to between at or about 45° C.and at or about 85° C., for example, to at or about 45° C., 46° C., 47°C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C., 55° C., 56°C., 57° C., 58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64° C., 65°C., 66° C., 67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73° C., 74°C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82° C., 83°C., 84° C. or 85° C. Typically, the heating apparatus is used to heatthe mixtures to a temperature of at or about 60° C.

The heating apparatus can be a water jacket, for example, a water jacketon a water-jacketed tank, which can be controlled, for example, by acontrol panel, such as to adjust the temperature of the contents of thetank. Other suitable heating apparatuses are immersible and/orsubmersible heaters, for example, 12 KW or 13 KW sanitary heaters,including food-grade heaters, that can be immersed into the tanks,typically while mixing and typically when higher temperatures arerequired, such as when temperatures greater than 60° C. or about 60° C.,or greater than 80° C. or about 80° C. are required. The heatingapparatuses also include stoves, for example, propane stoves, and hotplates, for example, Thermolyne® hot plates (e.g., Model Nos. 846925 andSP46615).

The cooling apparatus can be any apparatus that can cool the ingredientsand combinations thereof, such as rapidly cooling and/or cooling whilemixing the ingredients. Typically, the cooling apparatus is capable ofcooling the mixtures to a temperature between at or about 25° C. and ator about 45° C., for example, to at or about 25° C., 26° C., 27° C., 28°C., 29° C., 30° C., 31° C., 32° C., 33° C., 34° C., 35° C., 36° C., 37°C., 38° C., 39° C., 40° C., 41° C., 42° C., 43° C., 44° C. or 45° C. Insome examples, the cooling apparatus can cool the mixture to atemperature between at or about 30° C. and at or about 35° C. Typically,the cooling is rapid cooling. For example, the products can be cooled toa temperature between at or about 30° C. and at or about 35° C. in at orabout 15 minutes to at or about 2 hours, for example, in at or about 30minutes to at or about 60 minutes, such as in at or about 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes. In an exemplarymethod, the products can be cooled to a temperature between at or about30° C. to at or about 35° C. in at or about 30 minutes to at or about 60minutes.

Suitable cooling apparatuses for used in the methods include chillers,for example, recirculating coolers. The cooling apparatuses can beattached to the vessel, such as remotely or by a tank mounted in thecooler, to repeatedly circulate fluid from the tank, through the chillerand back to the vessel, to rapidly cool and maintain the temperature ofthe mixture during mixing. Exemplary of cooling apparatuses that can beattached to the tank and used with the provided methods are open-loopchillers and closed-loop chillers, for example, those sold by Turmoil(West Swanzey, N.H.), such as Model No. OC-1000 RO. Suitable coolingapparatuses also include water baths and ice baths, for example, waterbaths and/or ice baths in which the vessel is placed, for example,during homogenizing. Other cooling apparatuses are well known by thoseof skill in the art and can be used with the provided methods.

f. Transfer Devices

Transfer devices can be used with the provided methods to transferliquid from one vessel to another vessel. Transfer devices can be usedin the methods to combine the phases and form the emulsion. For example,transfer device can be used to transfer the water phase from the waterphase vessel to the oil phase vessel or to transfer the oil phase fromthe oil phase vessel to the water phase vessel. Transfer devicesinclude, for example, transfer pumps and associated accessories (e.g.,fittings), including ball valves, sanitary fittings (for example,sanitary fittings sold by Granger, Inc. (Lake Forrest, Ill.)) andtransfer hoses (for example, hoses sold by Sani-Tech West (Oxnard,Calif.)), such as food grade hoses attached to a transfer pump, forexample, the food grade Sani-Tech® STHT-R-HD Braid-Reinforced Heavy DutySilicone Hose. Suitable transfer pumps include the Teel Pump (Model2P377B; Granger, Inc., Lake Forrest Ill.), a self-priming pump having apower rating of 2 HP, 60 Hz voltage, 208-230/460 AC, speed of 3450 rpm;and other pumps, such as self-priming pumps from Granger, Inc. Thetransfer device can also include equipment for manually transferring theliquid to another vessel, for example, by pouring, pipetting and/orother well-known methods of manually transferring liquids.

g. Evaluation Equipment

Evaluation equipment includes equipment that can be used to evaluateproperties of the products and/or phases of the products, such as thetemperature, pH, clarity, color, activity, smell and/or taste of theproducts. Suitable evaluation equipment includes pH and temperaturemeters, such as the pH and temperature meter sold by Hanna Instruments(Model No. HI 8314; Ann Arbor, Mich.), which can be used to measure thetemperature and the pH of the product. Temperature meters can alsoinclude temperature probes, for example, digital and/or water-prooftemperature probes, such as temperature probes sold by Cooper-Atkins(Middlefield, Conn.), for example, the Cooper-Atkins digital waterprooftemperature probe (Model # DPP400W). The products can be evaluated andanalyzed to verify the amounts of the non-polar ingredients and toverify that the products meet industry standards, such as to verify thatthe products do not contain levels of microbials and heavy metals thatare above acceptable levels. Typically, these tests are performed bysending a sample of the product to a commercial testing facility, asdescribed in section 2(g), below.

2. General Methods for Producing the Compositions

In general, the methods useful for making the concentrates providedherein are performed by generating an oil phase and generating a waterphase (for the liquid nanoemulsion concentrates) and combining (e.g.,using a transfer device) and mixing the phases to form emulsions. Theoil and water phases typically are generated in separate vessels. Thevessels can be, for example, tanks. Generation of the water phase andgeneration of the oil phase can be performed simultaneously orsequentially, in any order. Typically, both phases are heated to adesired temperature prior to combining the phases. For example, thephases can be heated to 60° C. prior to combining the phases. Theprovided methods can include additional steps. In some examples, theadditional steps include evaluating properties of the products, addingadditional ingredients (e.g., taste-modifying agents), packaging and/orfiltering.

The provided methods can be performed using a bench-top manufacturingprocess (for small batch sizes) or performed using a scaled-upmanufacturing process (for larger batch sizes). Each of the providedproducts can be made with either the bench-top or scaled up process. Inone example, the product is first made with the bench-top process andthen the method is scaled up to make larger quantities of the product.

The bench-top process can be performed on a bench, counter, table or anyother suitable surface. Typically, the bench-top process is used to makeemulsions having relatively smaller volumes than those made with thescaled-up process. For example, volumes less than 1 L or about 1 L, orless than 1 gallon or about 1 gallon, for example, less than or about500 mL, for example, less than or about 1000 mL, 900 mL, 800 mL, 700 mL,600 mL, 500 mL, 450 mL, 400 mL, 350 mL, 300 mL, 250 mL, 200 mL, 150 mL,100 mL, or 50 mL or less, can be made using the bench-top process.

For the bench-top process, the equipment can be sufficiently compact tobe used on a bench-top or other similar surface, and can be sufficientlycompact to be moved, for example, lifted, by the artisan using themethods. For example, the vessels, such as water phase vessels, oilphase vessels, holding vessels, and packaging vessels, can be bench-topvessels. Exemplary bench-top vessels include, for example, flasks,beakers, vials, measuring containers, bottles and/or other bench-topcontainers. In some examples, the vessel in the bench-top process is aPyrex® beaker.

Typically, the mixers for use in the bench-top processes of the providedmethods are mixers that can be used in the bench-top vessels. Mixersthat can be used in the bench-top vessels include, for example, standardmixers, such as hand-held mixers, stir rods, stir bars, magnetic mixersand overhead mixers, including, for example, mechanical and/or electricoverhead mixers, and any other mixer that is suitable for use in thebench-top vessel. Exemplary standard mixers include those sold by IKA®,for example, overhead IKA® mixers, such as Model Nos. RW-14 Basic andRE-16S, which are laboratory stirrers and can be used to mixingredients, such as to generate the oil and water phases. Suitablebench-top mixers also include homogenizers, for example, reversiblehomogenizers. An exemplary reversible homogenizer is the Arde Barincoreversible homogenizer, Model no. CJ-4E, which can be used to emulsifythe phases.

Typically, the heating and cooling apparatuses are those that can beused with the bench-top vessels, such as hot plates, ice baths and/orwater baths, into (or onto) which the vessels can be placed, forexample, for rapid cooling. The evaluation device used in the bench-topprocess, for example, the temperature and/or pH meters, typically arecapable of being placed in the bench-top vessels.

For the bench-top process, combining the oil and water phases typicallyis carried out manually, e.g., by pouring, pipetting and/or anothermanual transfer device.

The scaled-up manufacturing process of the methods typically is used tomake products of relatively larger volumes, such as volumes greater than1 L or about 1 L, or greater than 1 gallon (gal) or about 1 gallon. Forexample, volumes greater than or about 0.5 L, for example, greater thanor about 0.5 L, 1 L, or 2 L, or greater than or about 1 gal, 2 gal, 3gal, 4 gal, 5 gal, 6 gal, 7 gal, 8 gal, 9 gal, 10 gal, 11 gal, 12 gal,13 gal, 14 gal, 15 gal, 16 gal, 17 gal, 18 gal, 19 gal, 20 gal, 21 gal,22 gal, 23 gal, 24 gal, 25 gal, 26 gal, 27 gal, 28 gal, 29 gal, 30 gal,40 gal, 50 gal, 60 gal, 70 gal, 80 gal, 90 gal, 100 gal, 150 gal, 200gal, 250 gal, 300 gal, 350 gal, 400 gal, 450 gal, 500 gal, 550 gal, 600gal, 650 gal, 700 gal, 800 gal, 900 gal, or 1000 gal or more, can bemade using the scaled-up manufacturing process.

In general, equipment used for the scaled-up process is compatible withlarger volume batches (batch sizes). For example, the vessels for use inthe scaled-up processes can be tanks, for example, water-jacketed tanks,which are equipped with water jackets that can be used as heatingapparatuses to heat the oil and water phase ingredients duringgeneration of the oil and water phases. The water jackets typically arecontrolled via control panels. The transfer device can include devicesattached to and connecting the tanks, such as transfer pumps andassociated fittings, for example, ball valves and hoses that areattached to the tanks. Mixers for use in the scaled-up process can bestandard mixers, for example, mounted mixers, such as LIGHTNIN® mixers,e.g., Model Nos. XJC117 (a fixed-mount, gear drive high-flow mixer) andND2.

Prior to beginning the methods, the water jacket lines on anywater-jacketed oil phase and water phase tank can be bled. The waterjacket switches can then be turned on to maintain a pressure in thewater jackets of between at or about 20 psi and at or about 40 psi(pounds per square inch). If the pressure in the water jacket fallsbelow 20 psi during the method, the line can be bled and checked forbubbles while purging the line.

a. Water Phase Ingredients

The water phase includes one or more polar solvents, such as water,diols, such as propylene glycol and sugar alcohols, such as glycerin,and, in some examples includes other water phase ingredients. Typically,water phase ingredients are hydrophilic and/or amphipathic ingredientsof the liquid nanoemulsion concentrate. For example, oils and otherlipophilic ingredients typically are not added to the water phase.Certain ingredients, for example, ingredients having hydrophobic andhydrophilic moieties, for example, surfactants and co-surfactants, canbe added to either the oil or the water phase, or to the oil and thewater phase. Exemplary water phase ingredients include, but are notlimited to, polar solvents, e.g., water, typically filtered water,propylene glycol, glycerin and other diols; emulsion stabilizers; pHadjusters, for example, phosphoric acid and/or citric acid; flavors;surfactants; co-surfactants, for example, phosphatidylcholine andsucrose fatty acid esters; and preservatives.

Water phase ingredients can be added to the water phase simultaneouslyand/or sequentially, in a specific order. In one example, one or morewater phase ingredients is added first and heated, prior to addition offurther ingredient(s). In one example, when the water phase ingredientsinclude a polar solvent and an emulsion stabilizer, these ingredientsare added sequentially, in the following order: 1) polar solvent, and 2)emulsion stabilizer. In one example, when the water phase ingredientsinclude water and an emulsion stabilizer, these ingredients are addedsequentially, in the following order: 1) water, and 2) emulsionstabilizer. In another example, when the water phase ingredients includea surfactant, a polar solvent (e.g., water) and an emulsion stabilizer,these ingredients are added to the water phase vessel sequentially, inthe following order: 1) surfactant; 2) polar solvent (e.g., water); and3) emulsion stabilizer. Alternatively, the water phase ingredients canbe added in any other order. Typically, when the water phase includes asurfactant, particularly when the surfactant is a surfactant that issolid at room temperature, for example, tocopherol polyethylene glycolsuccinate surfactant, the surfactant is the first water phase ingredientadded to the water phase vessel. Typically, when the water phaseingredients include an emulsion stabilizer, the emulsion stabilizer isthe last ingredient added to the water phase vessel.

b. Water Phase Production

To produce the water phase, appropriate amounts of the water phaseingredients are added to the water phase vessel. Water phase vessels caninclude tanks, for example, water-jacketed tanks such as, but notlimited to, the Overly 550 gallon water-jacketed tank, or any other tankdescribed herein. The amounts of the water phase ingredients aremeasured, e.g., weighed, either prior to adding to the water phasevessel or are measured in the water phase vessel. In one example, thewater phase ingredients are measured by weighing the ingredients on ascale (e.g., one or more of the scales described herein; the choice ofscale depends on the desired amount of the ingredient), before additionto the water phase vessel. Typically, the appropriate amount of thewater phase ingredient is calculated based on the desired concentration(e.g., weight/weight (w/w), molarity (M), volume/weight (v/w) orvolume/volume (v/v)), of the ingredient in the final product.

Water phase ingredients can include water, typically purified water. Inone example, unpurified water, for example, city water, is purified toremove impurities using one or more purifiers (e.g., purifiers describedherein) prior to adding it to the water phase vessel. In anotherexample, unpurified water, for example, city water, is purified bypassing the water through the following purifiers, typicallysequentially, in the following order: a carbon filter, an ion exchangepurifier, a reverse osmosis purifier and an end-point filter, forexample, a 100 micron end-point filter.

In general, the water phase ingredients are added, mixed and/or heatedin the water phase vessel. The water phase vessel can be a water phasetank, for example, a water-jacketed tank, such as one of the tanksdescribed herein (e.g., an Overly 550 gallon water-jacketed tank). Inone example, ingredients are heated to temperatures between at or about45° C. and at or about 85° C., for example, to at or about 45° C., 46°C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C., 55°C., 56° C., 57° C., 58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64°C., 65° C., 66° C., 67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73°C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82°C., 83° C., 84° C. or 85° C. In one example, the water phase ingredientsare heated to a temperature of at or about 60° C., for example, byadjusting the temperature on a water-jacketed tank or using anotherheating apparatus.

The mixing can be carried out with a standard mixer, a homogenizer, orany other suitable mixer, such as, but not limited to, the mixersdescribed herein. Exemplary mixers include standard mixers, such asLightnin® mixers (e.g., Model No. XJC117, a fixed-mount gear drivehigh-flow mixer) and homogenizers, such as Arde Barinco reversiblehomogenizers (e.g., Model No. CJ-4E). The mixer can be attached to thetop of the water phase vessel, for example, attached to the tank, suchas mounted on the top of the tank.

The water phase ingredients can be added to the water phasesimultaneously or sequentially in any order. Typically, the water, e.g.,purified water, is added before adding the other water phaseingredients. In one example, one or more of the ingredients are mixedand/or heated in the water phase tank before adding the other waterphase ingredients.

In an exemplary method provided herein, the water phase is generated bycombining water, e.g., purified water, and a preservative in the waterphase vessel. The water phase is then mixed using a mixer such as ahomogenizer, for example an Arde Barinco reversible homogenizer (e.g.,Model No. CJ-4E), typically using the “reverse” setting. The homogenizercan be attached to the top of the water phase vessel. The water phasemixture is then heated to the desired temperature, for example, to atemperature of at or about 60° C. After the mixture of water phaseingredients reaches the desired temperature, e.g., at or about 60° C.,an emulsion stabilizer, such as the SALADIZER® brand emulsion stabilizer(blend of xanthan gum, guar gum and sodium alginate) is added to thewater phase. The water phase mixture is then mixed, for example, using ahomogenizer, until the ingredients are mostly dispersed. Additionalwater phase ingredients are then added to the water phase tank at atemperature of at or about 60° C. The mixture is then mixed until theingredients are dispersed, using a mixer, such as a standard water phasemixer, for example, a Lightnin® mixer (e.g., Model No. XJC117).Typically the heat is maintained at a temperature of at or about 60° C.Typically, the ingredients are mixed until combined and maintained atthe desired temperature e.g., at or about 60° C., until combining withthe oil phase.

c. Oil Phase Ingredients

The oil phase includes the high dimer-containing water-soluble vitamin Ederivative surfactant, e.g., TPGS, the non-polar ingredient(s), forexample, non-polar ingredients that are or contain non-polar compoundsand, in some examples, other oil phase ingredients. Typically, oil phaseingredients include one or more lipophilic and/or amphipathicingredients of the liquid nanoemulsion concentrate. Oil phaseingredients typically do not include aqueous ingredients or hydrophilicingredients. Certain ingredients, for example, ingredients havinghydrophobic and hydrophilic moieties, for example, surfactants andco-surfactants, can be added to either the oil or the water phase, or tothe oil and the water phase. Exemplary of ingredients used in the oilphase of the provided concentrates are non-polar ingredients, forexample, non-polar ingredients that are or contain non-polar compounds,including any of the non-polar compounds or ingredients provided herein;emulsion stabilizers, pH adjusters, for example, phosphoric acid and/orcitric acid; surfactants; co-surfactants, for example,phosphatidylcholine and/or sucrose fatty acid esters; preservatives, andoils, for example, non-polar solvents and other oil phase ingredients.

Oil phase ingredients can be added to the oil phase simultaneouslyand/or sequentially, for example, in any order or in a specific order.In one example, one or more oil phase ingredients is added first andheated, prior to addition of further ingredient(s). In one example, whenthe oil phase ingredients include a surfactant, a preservative, asolvent, a co-surfactant, and a non-polar ingredient, these ingredientsare added sequentially, in the following order: 1) surfactant; 2)preservative; 3) solvent; 4) co-surfactant; 5) non-polar ingredient; and6) emulsion stabilizer. In another example, when the oil phaseingredients include a surfactant, a preservative and a non-polaringredient, the ingredients are added sequentially, in the followingorder: 1) surfactant; 2) preservative; and 3) non-polar ingredient. Inanother example, when the oil phase ingredients include a surfactant, apreservative, a non-polar ingredient and an emulsion stabilizer, theingredients are added sequentially, in the following order: 1)surfactant; 2) preservative; 3) non-polar ingredient; and 4) emulsionstabilizer. Alternatively, the oil phase ingredients can be added in adifferent order, for example, any order. Two or more oil phaseingredients can be added simultaneously.

Typically, when the oil phase includes a surfactant, particularly whenthe surfactant is a surfactant that is solid at room temperature, forexample, tocopherol polyethylene glycol succinate surfactant, thesurfactant is the first oil phase ingredient added to the oil phasevessel. Typically, when the oil phase ingredients include an emulsionstabilizer, the emulsion stabilizer is the last ingredient added to theoil phase vessel. Typically, the non-polar ingredient either is the lastingredient added to the oil phase vessel, or is added immediately priorto addition of the emulsion stabilizer, which is the last ingredientadded to the oil phase vessel.

d. Oil Phase Production

To produce the oil phase, appropriate amounts of the oil phaseingredients are added to the oil phase vessel. Oil phase vessels caninclude tanks, for example, water-jacketed tanks, such as, but notlimited to, the Royal 190 Gallon water-jacketed tank, or any other tankdescribed herein. The amounts of the oil phase ingredients are measured,e.g., weighed, either prior to adding to the oil phase vessel or areweighed/measured in the oil phase vessel. In one example, the oil phaseingredients are measured by weighing the ingredients on a scale (e.g.,one or more of the scales described herein; the choice of scale dependson the desired amount of the ingredient), before addition to the oilphase vessel. Typically, the appropriate amount of the oil phaseingredient is calculated based on the desired concentration (e.g.,weight/weight (w/w), molarity (M), volume/weight (v/w) or volume/volume(v/v)), of the ingredient in the final product.

In general, the oil phase ingredients are added, mixed and/or heated inthe oil phase vessel. Mixing the oil phase ingredients can be carriedout with a standard mixer or other mixer, such as, but not limited to,the mixers described herein, for example, a Lightnin® mixer (e.g., ModelNo. XJC117, a fixed-mount gear drive high-flow mixer). Heating the oilphase ingredients is carried out using a heating apparatus, such asthose described herein, typically a water jacket on a water-jacketedtank. In one example, the ingredients are heated to temperatures betweenat or about 45° C. and at or about 85° C., for example, to at or about45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C.,54° C., 55° C., 56° C., 57° C., 58° C., 59° C., 60° C., 61° C., 62° C.,63° C., 64° C., 65° C., 66° C., 67° C., 68° C., 69° C., 70° C., 71° C.,72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C.,81° C., 82° C., 83° C., 84° C. or 85° C. In one example, the oil phaseingredients are heated to a temperature of at or about 60° C., forexample, by adjusting the temperature on a water-jacketed tank.

The oil phase ingredients can be added to the oil phase vesselsimultaneously or sequentially in any order. In one example, one or moreof the ingredients are added, mixed and/or heated, prior to the additionof the other ingredients to the vessel.

In an exemplary method provided herein, the oil phase is generated bycombining an oil, such as a fatty acid (e.g., coconut oil) and astimulant (e.g., theobromine) in the oil phase vessel. The oil phase isthen heated to the desired temperature, for example, to a temperature ofat or about 60° C., by adjusting the temperature on a water-jacketedtank, until dissolved. After the mixture of oil phase ingredientsreaches the desired temperature, e.g., at or about 60° C., a surfactant,for example, TPGS, such as the TPGS compositions described herein isadded to the oil phase. In some examples, the oil phase ingredients aremixed (e.g., using a mixer as provided herein) during generation of theoil phase. Typically, the oil phase ingredients are mixed until combinedand maintained at the desired temperature, e.g., at or about at 60° C.,prior to combining with the water phase.

e. Combining Phases

After the oil phase and the water phase are generated, the phases can becombined, for example, by using a transfer device, and mixed, e.g.,homogenized, to form an emulsion. In one example, the oil phase istransferred from the oil phase vessel to the water phase vessel. Inanother example, the water phase is transferred from the water phasevessel to the oil phase vessel. In another example, the oil and waterphases are transferred to another vessel, such as an emulsifying vessel.

Transfer device can include any device for transferring the contents ofone vessel to another vessel, as described above. For example, suitabletransfer device include transfer pumps and associated equipment, suchas, but not limited to, combinations of sanitary fittings, hoses and/orball valves; manual transfer device, for example, pouring and/orpipetting device; and any other suitable transfer device known to thoseof skill in the art. Typically, the phases are kept clean, e.g.,sterile, during transfer. Sterility of the phases can be maintained, forexample, by transfer device having sanitary fittings and/or by combiningthe phases in a sterile environment. In one example, the transfer deviceinclude a transfer pump, for example, a Teel pump (Model No. 2P377B;Granger, Inc.), sanitary fittings, transfer hoses, for example, foodgrade hoses, such as those sold by Sani-Tech West, and ball valves,which are attached to the tanks and connect the tanks.

Simultaneous with and/or subsequent to the combination of the phases, amixer, for example, a homogenizer (e.g., a reversible homogenizer), canbe used to emulsify the water and oil phases. In one example, ahomogenizer, e.g., a homogenizer mounted on one of the tanks, is turnedon, the ball valves are opened, and the transfer pump is turned on toeffect transfer of the contents of one tank to another, for example, totransfer the contents of the oil phase tank to the water phase tank. Asthe phases are combined, they can be mixed by the homogenizer to form anemulsion. The position of the homogenizer in the tank can be adjusted,for example, by adjusting a baffle plate, e.g., moving the baffle platefurther into/out of the mixture, in order to achieve and maintain theemulsion. Typically, the phases are homogenized (i.e., emulsified) byoperating the mixer, e.g., homogenizer, at a speed sufficient to form anemulsion. In one example, the homogenizer is operated at a speed ofbetween at or about 1000 and at or about 1500 rpm. Mixing typically iscontinued until the phases are combined, typically in an emulsion.

f. Cooling

The emulsion can be cooled during and/or after mixing to promotestability and emulsification, for example, by preventing or minimizingoxidization. The cooling can be rapid cooling and can be performed usingone or more cooling apparatuses, for example, any of the coolingapparatuses described herein or any cooling apparatus known to those ofskill in the art. Suitable cooling apparatuses for use with the methodsinclude recirculating coolers and water and ice baths. An exemplarycooling apparatus is a recirculating cooler, such as those sold byTurmoil (Model No. OC-1000 RO; West Swanzey, N.H.). When the coolingapparatus is a recirculating cooler, fluid from the vessel containingthe combined oil and water phases is circulated through the cooler,typically while mixing, and then back to the vessel, to rapidly cool andmaintain the temperature of the mixture during mixing. Typically, thephases are mixed and cooled until the phases are emulsified and thetemperature of the emulsification reaches between at or about 25° C. andat or about 43° C., typically between at or about 30° C. and at or about35° C. For example, the emulsification can be cooled to a temperature ofat or about 25° C., 26° C., 27° C., 28° C., 29° C., 30° C., 31° C., 32°C., 33° C., 34° C., 35° C., 36° C., 37° C., 38° C., 39° C., 40° C., 41°C., 42° C. or 43° C. Typically, when the cooling is rapid cooling, thetemperature can be reached in less than or about 2 hours, typically lessthan or about 1 hour. For example, the emulsification can be cooled tothe desired temperature, e.g., between at or about 25° C. and at orabout 43° C., in at or about 30 minutes to at or about 60 minutes, suchas in at or about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60minutes.

Cooling can be performed before or after additional steps, such asadding additional ingredients and/or evaluation of the product. In oneexample, the cooling is carried out after the addition of additionalingredients, for example, taste-modifying agents, and/or pH adjustingagents.

g. Filtration, Additions, Evaluation and Packaging

After combining the oil and water phases to form a mixture, i.e.,emulsion, one or more additional steps can be carried out to modify,evaluate, analyze and/or package the product. Typically, taste-modifyingagents are added to the emulsion, such as flavoring agents (e.g.,flavoring agents that confer fruit flavors, such as peach, or otherflavors, such as pina colada) and sweetening agents (e.g., sucralose).Other ingredients can be added, such as masking agents (e.g., NATmasking agent) and pH adjusting agents (e.g., acids, such as, but notlimited to citric acid). The pH adjusting agent can be used to adjustthe pH of the emulsion, for example, to a pH of between at or about 2and at or about 5, e.g., to at or about 2 and at or about 3.5. Thus, theprovided products typically have a pH of between at or about 2 and at orabout 5, e.g., at or about 2 and at or about 3.5, such as a pH of at orabout 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2,3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6,4.7, 4.8, 4.9 or 5.

Before and/or after adding additional ingredients, the product can beevaluated, such as by measuring the pH and/or the temperature.Measurements can be taken using an instrument such as those describedherein. In one example, additional ingredients (e.g., pH adjusters) areadded based on information obtained by evaluating the product. Theproduct can be analyzed and evaluated to verify and/or determine otherproperties of the product, for example, to verify that the productcontains the appropriate amounts of the non-polar ingredients and otheringredients. For example, the products can be evaluated to verify thatmicrobial and heavy metal (e.g., arsenic, cadmium, mercury, lead andothers) levels are within the acceptable range according to food andbeverage standards. In one example, the acceptable microbial levels arenot more than 1,000 cfu/g microbes (e.g., yeast, bacteria, mold andother microbes) and negative for E. coli and Salmonella. In anotherexample, the acceptable heavy metal levels are not more than 10 ppmheavy metals and not more than 0.2 ppm lead and 2 ppm arsenic. When astandard exists for a particular amount and/or property, theamount/property is verified by tests in accordance with U.S.Pharmacopeia (USP) and/or AOAC (Association of Analytical Communities)standards. Samples can be analyzed in accordance with these standards bysending a sample of the product to a commercial testing facility, suchas Eurofins U.S. (Des Moines, Iowa) or Advanced Botanical Consulting &Testing, Inc. (Tustin, Calif.), or any other facility that performstests in accordance with these standards.

For example, the amount of some non-polar ingredients, such as caffeineanhydrous, chromium picolinate and vitamin B12, typically is verifiedaccording to USP standards. The density and pH of the composition andthe level of microbes, e.g., yeast, mold, E. coli and Salmonella, alsotypically are verified according to USP standards. The amount of fattyacids, e.g., coconut oil, can be verified according to AOAC standards,for example, by gas chromatography (GC), gas liquid chromatography (GLC)or other fatty acid profiling methods. The levels of heavy metals, suchas lead and arsenic, are tested using inductively coupled plasma massspectrometry (ICP-MS), or by sending a sample of the composition fortesting to a testing facility, such as Eurofins U.S. (Des Moines, Iowa)or Advanced Botanical Consulting & Testing, Inc. (Tustin, Calif.), orany other facility capable of performing such tests. Additionally,Fourier transform infrared spectroscopy (FTIR) typically is used toobtain a fingerprint of the product, to verify that no other compoundsexcept the desired ingredients are present in the product.

The emulsifications can be purified, for example, filtered, prior touse, using any of purification device described herein or any othersuitable purification device. Water can be added in the case ofevaporation, to bring the product up to the appropriate volume. HPLC,GC, GLC, FTIR and ICP-MS can be performed according to well-knownmethods (see, for example, Analytical Chemistry: An Introduction, 6thEd., Douglas A. Skoog et al. (1994) Chapters 22 (FTIR) and 27 (GC/GLC,HPLC) and U.S. Pat. No. 6,265,717 (ICP-MS)).

After evaluation, purification, and/or addition of all the ingredients,the product can be packaged, for example, into large containers forstorage or into smaller containers for administration, such as bottlesor ampoules (as described below). The products can be transferred to thepackaging containers using a transfer device, such as the transferdevice described herein, including transfer pumps and fittings asdescribed above or by manual transfer. For example, the product can bepackaged for storage in containers, such as totes, e.g., 275 gallontotes (such as the 275 gallon bottle with a reconditioned CageTote tankIBC, Item No. REN275; Qualsery Enterprises, Inc.(www.qualservcontainer.com)), by transferring the mixture using a foodgrade hose (Sani-Tech® STHT-R-HD braid-reinforced heavy duty siliconehose; Sani-Tech West). After transfer, the tote can be closed andsealed, e.g., tied, such as with a cable tie.

h. Cleaning the Equipment

The equipment used in the provided methods can be cleaned prior to, andtypically after, use. For example, the methods include cleaning all theequipment in a sink and/or rinsing the vessels, e.g., tanks, and hoselines. The tanks can be cleaned by filling with hot water, washing withsoap and water, rinsing with water. The pH of the water can be checkedbefore discharging the water from the vessel. The water can be adjustedto the desired pH, for example to a pH between 6 and 9, by adding a pHadjusting agent, such as soda ash, citric acid and/or H₃PO₄. Afterdischarging the water from the vessel, the tanks can be sanitized, suchas with isopropyl alcohol (IPA), and let dry.

i. Clarity

Compositions containing the high dimer-containing PEG derivative ofvitamin E mixture, such as TPGS, are more clear (less turbid) thancompositions containing the high monomer PEG derivative of vitamin E,such as TPGS, such as that available from Eastman Chemical Company, asdescribed herein. The clarity of each of the compositions containing theconcentrates that contained the high dimer (about 51%) TPGS mixture(composition), prepared according to Example 1 below, was determined andcompared to the clarity of the concentrates that contained thecommercially available standard TPGS composition (low dimer-containing)from Eastman.

The clarity of each concentrate was evaluated by a turbidity analysisusing a nephelometer. The concentrates were prepared for the analysisusing the following steps. Eight ounces of water was heated in a Pyrex®beaker by placing the beaker on a Thermolyne hot plate (Model #846925)until the water reached 49.8° C. The concentrate was then added to theheated water and stirred with a stir rod until dispersed. The resultingaqueous composition was cooled to room temperature (about 25° C.). Thecooled aqueous composition was added to an amber-glass screw-top vial(Alcon) for evaluation. The vials that contained the aqueouscompositions were sent to ACZ Laboratories, Inc. (Steamboat Springs,Colo.) for turbidity analysis using a nephelometer. Results of theanalysis are listed in the form of Nephelometric Turbidity Units (NTU)and are indicated in Tables A-C below.

TABLE A Turbidity (NTU) of aqueous compositions containing 10% fish oilComposition Turbidity (NTU) TPGS (Example 1) + 10% fish oil 12.1 TPGS(Eastman) + 10% fish oil 76.8

TABLE B Turbidity (NTU) of aqueous compositions containing 15% fish oilComposition Turbidity (NTU) TPGS (Example 1) + 15% fish oil 38.5 TPGS(Eastman) + 15% fish oil 233

TABLE C Turbidity (NTU) of aqueous compositions containing 20% fish oilComposition Turbidity (NTU) TPGS (Example 1) + 15% fish oil 718 TPGS(Eastman) + 15% fish oil 1000

As the data demonstrate, aqueous compositions that contained the liquidnanoemulsion concentrates that were prepared with the highdimer-containing TPGS composition, prepared as described in Example 1(i.e., TPGS compositions that contained the higher amounts of TPGS dimerand lower amounts of TPGS monomer), exhibited significantly lowerturbidity than those compositions that contained the liquid nanoemulsionconcentrates prepared using commercially available TPGS (i.e., TPGScompositions that contained higher amounts of TPGS monomer and loweramounts of TPGS dimer). Additional data are provided in U.S. applicationSer. No. 14/207,310, now published as US-2014-0271593-A1.

3. General Methods for Preparing Aqueous Pre-Gel Concentrates(Compositions that are Introduced into or Formulated in Soft Gel Shellsor Capsules)

In general, the methods useful for making the pre-gel concentratesprovided herein are performed by combining the ingredients, i.e.,non-polar ingredients, non-aqueous solvents, and a surfactant, andmixing to form a homogenous pre-gel concentrate. The pre-gel concentratetypically is generated in a vessel. The vessel can be, for example, atank. Typically, the mixture is heated to a desired temperature to forma homogenous mixture. For example, the mixture can be heated to 60° C.The provided methods can include additional steps. In some examples, theadditional steps include evaluating properties of the pre-gelconcentrates, adding additional ingredients, packaging and/or filtering.

The provided methods can be performed using a bench-top manufacturingprocess (for small batch sizes) or performed using a scaled-upmanufacturing process (for larger batch sizes). Each of the providedpre-gel concentrates can be made with either the bench-top or scaled upprocess. In one example, the pre-gel concentrate is first made with thebench-top process and then the method is scaled up to make largerquantities of the product.

The bench-top process can be performed on a bench, counter, table or anyother suitable surface. Typically, the bench-top process is used to makepre-gel concentrates having relatively smaller volumes than those madewith the scaled-up process. For example, volumes less than 1 L or about1 L, or less than 1 gallon or about 1 gallon, for example, less than orabout 500 mL, for example, less than or about 1000 mL, 900 mL, 800 mL,700 mL, 600 mL, 500 mL, 450 mL, 400 mL, 350 mL, 300 mL, 250 mL, 200 mL,150 mL, 100 mL, or 50 mL or less, can be made using the bench-topprocess.

For the bench-top process, the equipment can be sufficiently compact tobe used on a bench-top or other similar surface, and can be sufficientlycompact to be moved, for example, lifted, by the artisan using themethods. For example, the vessels can be bench-top vessels. Exemplarybench-top vessels include, for example, flasks, beakers, vials,measuring containers, bottles and/or other bench-top containers. In someexamples, the vessel in the bench-top process is a Pyrex® beaker.

Typically, the mixers for use in the bench-top processes of the providedmethods are mixers that can be used in the bench-top vessels. Mixersthat can be used in the bench-top vessels include, for example, standardmixers, such as hand-held mixers, stir rods, stir bars, magnetic mixersand overhead mixers, including, for example, mechanical and/or electricoverhead mixers, and any other mixer that is suitable for use in thebench-top vessel. Exemplary standard mixers include those sold by IKA®,for example, overhead IKA® mixers, such as Model Nos. RW-14 Basic andRE-16S, which are laboratory stirrers and can be used to mixingredients, such as to for a homogenous concentrate. Suitable bench-topmixers also include homogenizers, for example, reversible homogenizers.An exemplary reversible homogenizer is the Arde Barinco reversiblehomogenizer, Model no. CJ-4E.

Typically, the heating and cooling apparatuses are those that can beused with the bench-top vessels, such as hot plates, ice baths and/orwater baths, into (or onto) which the vessels can be placed, forexample, for rapid cooling. The evaluation device used in the bench-topprocess, for example, the temperature and/or pH meters, typically arecapable of being placed in the bench-top vessels.

The scaled-up manufacturing process of the methods typically is used tomake pre-gel concentrates of relatively larger volumes, such as volumesgreater than 1 L or about 1 L, or greater than 1 gallon (gal) or about 1gallon. For example, volumes greater than or about 0.5 L, for example,greater than or about 0.5 L, 1 L, or 2 L, or greater than or about 1gal, 2 gal, 3 gal, 4 gal, 5 gal, 6 gal, 7 gal, 8 gal, 9 gal, 10 gal, 11gal, 12 gal, 13 gal, 14 gal, 15 gal, 16 gal, 17 gal, 18 gal, 19 gal, 20gal, 21 gal, 22 gal, 23 gal, 24 gal, 25 gal, 26 gal, 27 gal, 28 gal, 29gal, 30 gal, 40 gal, 50 gal, 60 gal, 70 gal, 80 gal, 90 gal, 100 gal,150 gal, 200 gal, 250 gal, 300 gal, 350 gal, 400 gal, 450 gal, 500 gal,550 gal, 600 gal, 650 gal, 700 gal, 800 gal, 900 gal, or 1000 gal ormore, can be made using the scaled-up manufacturing process.

In general, equipment used for the scaled-up process is compatible withlarger volume batches (batch sizes). For example, the vessels for use inthe scaled-up processes can be tanks, for example, water-jacketed tanks,which are equipped with water jackets that can be used as heatingapparatuses to ingredients during generation of the pre-gel concentrate.The water jackets typically are controlled via control panels. Thetransfer device can include devices attached to and connecting thetanks, such as transfer pumps and associated fittings, for example, ballvalves and hoses that are attached to the tanks. Mixers for use in thescaled-up process can be standard mixers, for example, mounted mixers,such as LIGHTNIN® mixers, e.g., Model Nos. XJC117 (a fixed-mount, geardrive high-flow mixer) and ND2.

Prior to beginning the methods, the water jacket lines on anywater-jacketed oil phase and water phase tank can be bled. The waterjacket switches can then be turned on to maintain a pressure in thewater jackets of between at or about 20 psi and at or about 40 psi(pounds per square inch). If the pressure in the water jacket fallsbelow 20 psi during the method, the line can be bled and checked forbubbles while purging the line.

a. Ingredients

The pre-gel concentrates include a surfactant, for example, apolyalkylene glycol derivative of vitamin E, e.g., TPGS, the non-polaringredients, for example, non-polar ingredients that are or containnon-polar compounds, and non-aqueous solvents. Typically, theingredients do not include aqueous ingredients, e.g., water. Exemplaryof ingredients used in the provided pre-gel concentrates are non-polaringredients, for example, non-polar ingredients that are or containnon-polar compounds, including any of the non-polar compounds andingredients provided herein; surfactants, including any of thepolyalkylene glycol derivatives of vitamin E provided herein; andnon-aqueous solvents, for example, solvents that have no watersolubility or are only partially solubility in water.

b. Production of the Non-Aqueous Pre-Gel Concentrates

Typically, the ingredients are weighed and/or measured, for example,using one or more scales (e.g., one or more of the scales describedherein), before they are added to the mixing vessel (e.g., any vesseldescribed herein). In one example, the amount of each ingredient to beadded is determined according to the provided methods for formulatingthe pre-gel concentrates. Typically, the desired concentration, byweight (w/w), of the final pre-gel concentrate is used to calculate theamount of each ingredient that is added to the vessel. Alternatively,the desired volume per weight, volume per volume or weight per volumecan be used to calculate the correct amount of an ingredient to bemeasured and added to the vessel.

The ingredients can be added simultaneously and/or sequentially, forexample, in any order or in a specific order. In one example, one ormore ingredients are added first and heated, prior to addition offurther ingredient(s). Typically, when the ingredients include asurfactant, a non-aqueous solvent and a non-polar ingredient, theingredients are added sequentially, in the following order: 1)surfactant; 2) non-aqueous solvent; 3) non-polar ingredient.Alternatively, the ingredients can be added in a different order, forexample, any order. Two or more ingredients can be added simultaneously.

Typically, when the oil phase includes a surfactant, particularly whenthe surfactant is a surfactant that is solid at room temperature, forexample, a tocopherol polyethylene glycol succinate surfactant, thesurfactant is the first ingredient added to the vessel. Typically, thenon-polar ingredients are the last ingredients added to the vessel.

Typically, in order to dissolve the ingredients, the ingredients aremixed in the mixing vessel using a standard mixer (e.g., any of thestandard mixers described herein) and heated using a heating apparatus(e.g., any of the heating apparatuses described herein). Typically, theingredients are heated such that the ingredients reach an elevatedtemperature, for example, between about 45° C. or about 45° C. and 85°C. or about 85° C., for example, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85° C., typically, 60°C. or about 60° C. Typically, the ingredients are heated at an elevatedtemperature, for example, at 60° C. or about 60° C., until theingredients dissolve, e.g., until a homogenous mixture is formed.

The ingredients typically are homogenized, continuously orintermittently, until the ingredients become homogeneous at the elevatedtemperature, for example, at between about 45° C. or about 45° C. and85° C. or about 85° C., for example, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85° C., typically,60° C. or about 60° C. In one example, the baffle plate of the mixer isadjusted, for example, by moving the baffle plate further down into themixture or further up out of the mixture, to control the type of mixing,for example, to switch from downward flow to upward flow and vice versa,during mixing of the ingredients. In another example, the homogenizercan be adjusted to increase or decrease shear or to maintain the shearat a particular speed. Methods for homogenizing ingredients are wellknown and other methods can be used to homogenize in the providedmethods.

Typically, after all the ingredients have been added and madehomogeneous, the pre-gel concentrate is filtered using an end-productfilter (e.g., a 100 micron end-product filter), to remove anyimpurities.

c. Transfer and/or Packaging

After mixing, the pre-gel concentrate is transferred, using one or moretransfer means, to another vessel, for example, a holding or packagingvessel and/or a storage container. Any transfer means can be used. Forexample, any means for transferring the contents of one vessel toanother vessel as described above, for example, transfer pumps andassociated equipment, for example, sanitary fittings, hoses and/or ballvalves; and manual transfer means, for example, pouring and/or pipettingmeans or other known transfer means. In some examples, the mixture iskept clean, for example, sterile during transfer, for example, by usingtransfer means with sanitary fittings and/or combining the phases in asterile environment.

In one example, the mixture is transferred to a holding tank. In anotherexample, the pre-gel concentrate, after being made and filtered, istransferred, e.g., by hot filling while the concentrate is a liquid, toa storage container, e.g., a vial, plastic bottle, or bag-in-a-box typepackaging. Typically, the concentrate is allowed to cool naturally inthe storage container. Alternatively, a cooling apparatus, e.g., arefrigerator, freezer or water bath, can be used to cool the concentratein the storage container. The pre-gel concentrate can remain a liquid asit cools or, alternatively, can solidify or partially solidify as itcools in the storage container, e.g., becomes a waxy solid.

4. Exemplary Methods for Preparing Pre-Spray Emulsions and Powders

Methods for preparing the pre-spray emulsions include those describedabove and exemplified below for preparing emulsions. The powderscontaining a high amount of non-polar ingredients and a sugar fatty acidester-binder mixture are prepared by any suitable drying methods.Equipment for use in the methods and general steps of the methods aredescribed herein. The methods include bench-top manufacturing processes,which are used to make small quantities of the concentrates. The methodsalso include scaled-up manufacturing processes, which are used to makelarger batches of the compositions and powders. Any of the bench-topprocesses can be scaled up to perform the methods using the scaled-upprocesses. Any of the emulsions and powders can be made using eitherscaled-up or bench-top processes. For example exemplary methods includethose described in U.S. Pat. No. 8,282,977 and U.S. Pub. Nos.2009-0297491 and 2012-0016026.

a. General Methods for Producing the Emulsions and Powders

As described above, emulsions are prepared by generating an oil phase(e.g., the pre-emulsion concentrate) and generating a water phase andcombining (e.g., using a transfer device) and mixing the phases to formemulsions, e.g., the pre-spray emulsions. The dry powders are generatedfrom the pre-spray emulsions by drying, for example, by spray drying thepre-spray emulsions. The oil and water phases typically are generated inseparate vessels. The vessels can be, for example, tanks. Generation ofthe water phase and generation of the oil phase can be performedsimultaneously or sequentially, in any order. Typically, both phases areheated to a desired temperature prior to combining the phases. Forexample, the phases can be heated to between 60° C. and 70° C. prior tocombining the phases. The provided methods can include additional steps.In some examples, the additional steps include evaluating properties ofthe products, adding additional ingredients (e.g., taste-modifyingagents), packaging and/or filtering. The methods and equipment forpreparing the emulsions are as described above.

b. Drying the Emulsions to Produce Powders

After combining the oil phase and water phase to form the emulsion, theemulsion can be dried into a powder. The emulsion is dried, for example,spray dried, into a powder after the emulsion has been cooled to adesired temperature, e.g., between or between about 25° C. and 43° C.,such as at or about 30° C. The methods for forming the powders includespray drying. Spray drying processes and spray drying equipment aredescribed generally in Perry's Chemical Engineers' Handbook, pp. 20-57(Sixth Edition 1984). More details on spray drying processes andequipment are reviewed by Marshall (1954) “Atomization andSpray-Drying,” Chem. Eng. Prog. Monogr. 50: Series 2 and Masters, “SprayDrying Handbook” (Fourth Edition 1985). Methods for spray drying arewell known (see, e.g., U.S. Pat. Nos. 5,430,021 and 6,534,085 and U.S.Publication No. 2007/0184117). In general, spray drying is used to dry aheated liquid by passing it through hot gas. One or more spray nozzlesis used to atomize the liquid in a cooling tower or chamber. As thematerial is atomized (sprayed), the surface tension causes a uniformspherical particle to form, which is passed through the cooling chamberand hardens into a solid intact sphere. The spray dried particles can bebetween at or about 0.5 microns and at or about 100 microns, andtypically are less than at or about 10 microns, typically less than ator about 5 microns, and typically less than at or about, or at or about,1 micron.

Exemplary of a spray dryer is a cyclone spray dryer. During spray dryingwith a cyclone spray dryer, the homogenized mixture is pumped into anatomizing device where it is broken into small droplets. Upon contactwith a stream of hot air, the moisture is removed very rapidly from thedroplets while still suspended in the drying air. The dry powder isseparated from the moist air in cyclones by centrifugal action. Thecentrifugal action is caused by the great increase in air speed when themixture of particles and air enters the cyclone system. The dense powderparticles are forced toward the cyclone walls while the lighter, moistair is directed away through the exhaust pipes. The powder settles tothe bottom of the cyclone where it is removed through a dischargingdevice. Sometimes the air-conveying ducts for the dry powder areconnected with cooling systems which admit cold air for transport of theproduct through conveying pipes. Cyclone dryers have been designed forlarge production schedules capable of drying ton-lots of powder perhour.

The methods provided herein produce powders using a standard spraydryer. The liquid to be dried, for example a solution, suspension oremulsion, may be fed into an atomizer to generate the powder. Theatomizer may be, for example, a rotary (wheel) atomizer or nozzleatomizer. In some examples, a fluid bed dryer may also be used. Theatomizer is typically an open-mode design with single-point powderdischarge, an open-mode design with dual-point powder discharge, or aclosed-cycle design with single-point powder discharge, or analternative form of atomizer. In some examples, the atomizer iscontained within a dryer consisting of a feed pump to funnel in theliquid, for example the emulsion, an atomizer, an air heater, an airdispenser, a drying chamber, systems for powder recovery, and processcontrol systems.

In order to prepare the dry powder using a spray drier, the liquid,e.g., emulsion, is fed into a rotary wheel or high pressure nozzleatomizer at a uniform rate, and thereby converted into a spray ofdroplets. The pattern of the resultant droplets may be largely dependenton the properties of the liquid to be spray dried, including its bulkdensity, in conjunction with the speed and configuration of the atomizerwheel. In desirable conditions, rotation of the atomizer wheel occurswith minimal vibration, at high peripheral speeds and with smoothinternal surfaces, for maximum efficacy. The optimum speed and wheelconfiguration for a specific liquid can be determined empirically by oneof skill in the art. In some examples, the spray of droplets contactsthe hot air, for example air at a temperature of about 180° C., presentin the drying chamber, triggering the formation of dry particles andcooling of the hot air due to the evaporation of water or chemicalsolvent from the concentrated liquid sample. The resultant powder andcooler, humid air are separately, and continuously, discharged from thechamber. In some examples, the dry powder is cooled and bagged afterseparation from the cooler, humid air. After powder recovery, somepowders are rewet by re-dissolving the powder in water or a solvent andthe composition is subject to a second round of spray drying andcollection. In some examples the powders are then sifted, for examplethrough a 60-80 μm mesh screen.

As will be appreciated by one of skill in the art, the inlet temperatureand the outlet temperature of the spray drier are not critical but willbe of such a level to provide the desired particle size, of less than ator about 1 micron, and to result in a powder that has a desiredproperty. The inlet and outlet temperatures can be adjusted depending onthe melting characteristics and composition of the emulsion. The inlettemperature typically is between at or about 60° C. and at or about 170°C. with outlet temperatures between at or about 40° C. to at or about120° C. Typical inlet temperatures are from at or about 90° C. to at orabout 120° C. and typical outlet temperatures are from at or about 60°C. to at or about 90° C. The flow rate which is used in the spray dryingequipment will generally be at or about 3 mL per minute to at or about15 mL per minute. The atomizer air flow rate will vary between values ofat or about 25 L per minute to at or about 50 L per minute. Commerciallyavailable spray dryers are well known to those of skill in the art, andsuitable settings for any particular dispersion can be readilydetermined by one of skill in the art without undue experimentation.Operating conditions such as inlet temperature and outlet temperature,feed rate, atomization pressure, flow rate of the drying air, and nozzleconfiguration can be adjusted in accordance with the manufacturer'sguidelines.

In some examples, a processing aid, such as additional solvent, forexample, water, is added to the emulsion. The processing aid, e.g.,water, allows the emulsion to pass through the pump of the dryer moreeasily, for example, by making the emulsion less thick. The processingaid, for example, water, is evaporated during the spray drying processand is not present in the final dry powder.

The resulting powder can be processed further, such as by adding polarsolvent and repeating the drying process. This can improve to propertiesof the powders.

c. Storing the Powders

The resulting powders are very stable and can be stored in anyconvenient manner, including in packets, such as packets containing anamount for a single dose or use or multiple doses. The amount in eachpack depends upon the intended application.

In some examples, the dry powder is stored into a capsule form or ispressed into a tablet. For use as tablets, the compositions can containother excipients generally included in tables. These excipients includetablet disintegrants, such as corn starch, glidants, such as silicondioxide, and lubricants such as magnesium stearate. Ordinarily thesecompositions contain minor amounts by weight of glidants and lubricants,e.g., each two percent (2%) or less by weight. Tablet disintegrants areoptionally present and, if present, are included in sufficient amountsto assure that the tablet disintegrates upon ingestion. For example,disintegrants, such as corn starch, can be employed at concentrations offrom about zero to about 30 percent by weight of the composition.

The free-flowing, i.e., not sticky, powders also can be used toadminister the non-polar ingredients by inhalation using a dry powderinhaler (DPI). Such dry powder inhalers typically administer theingredient as a free-flowing powder that is dispersed in the air-streamduring inspiration. In order to achieve a free-flowing powder, theingredients are typically formulated with a suitable excipient such aslactose or starch. For example, such a dry powder formulation can bemade, for example, by combining the lactose with the non-polaringredient and then dry blending the components. Alternatively, ifdesired, the non-polar ingredient can be formulated without anexcipient. The pharmaceutical composition is then typically loaded intoa dry powder dispenser, or into inhalation cartridges or capsules foruse with a dry powder delivery device. Examples of dry powder inhalerdelivery devices include Diskhaler (GlaxoSmithKline, Research TrianglePark, N.C.) (see, e.g., U.S. Pat. No. 5,035,237); Diskus(GlaxoSmithKline) (see, e.g., U.S. Pat. No. 6,378,519; Turbuhaler(AstraZeneca, Wilmington, Del.) (see, e.g., U.S. Pat. No. 4,524,769);Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 4,353,365) andHandihaler (Boehringer Ingelheim). Further examples of suitable DPIdevices are described in U.S. Pat. Nos. 5,415,162, 5,239,993, and5,715,810 and references cited therein.

d. Filtration, Additions, Evaluation and Packaging

After combining the oil and water phases to form a mixture, i.e.,emulsion, or after spray drying the emulsion to form a dry powder, oneor more additional steps can be carried out to modify, evaluate, analyzeand/or package the product. Typically, taste-modifying agents are addedto the emulsion, such as flavoring agents (e.g., flavoring agents thatconfer fruit flavors, such as peach, or other flavors, such as pinacolada) and sweetening agents (e.g., sucralose). Other ingredients canbe added, such as masking agents (e.g., NAT masking agent) and pHadjusting agents (e.g., acids, such as, but not limited to citric acid).The pH adjusting agent can be used to adjust the pH of the emulsion, forexample, to a pH of between at or about 2 and at or about 5, e.g., to ator about 2 and at or about 3.5. Thus, the provided products typicallyhave a pH of between at or about 2 and at or about 5, e.g., at or about2 and at or about 3.5, such as a pH of at or about 2, 2.1, 2.2, 2.3,2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.

Before and/or after adding additional ingredients, the product can beevaluated, such as by measuring the pH and/or the temperature.Measurements can be taken using an instrument such as those describedherein. In one example, additional ingredients (e.g., pH adjusters) areadded based on information obtained by evaluating the product. Theproduct can be analyzed and evaluated to verify and/or determine otherproperties of the product, for example, to verify that the productcontains the appropriate amounts of the non-polar ingredients and otheringredients. For example, the products can be evaluated to verify thatmicrobial and heavy metal (e.g., arsenic, cadmium, mercury, lead andothers) levels are within the acceptable range according to food andbeverage standards. In one example, the acceptable microbial levels arenot more than 1,000 cfu/g microbes (e.g., yeast, bacteria, mold andother microbes) and negative for E. coli and Salmonella. In anotherexample, the acceptable heavy metal levels are not more than 10 ppmheavy metals and not more than 0.2 ppm lead and 2 ppm arsenic. When astandard exists for a particular amount and/or property, theamount/property is verified by tests in accordance with U.S.Pharmacopeia (USP) and/or AOAC (Association of Analytical Communities)standards. Samples can be analyzed in accordance with these standards bysending a sample of the product to a commercial testing facility, suchas Eurofins U.S. (Des Moines, Iowa) or Advanced Botanical Consulting &Testing, Inc. (Tustin, Calif.), or any other facility that performstests in accordance with these standards.

For example, the amount of some non-polar ingredients, such as caffeineanhydrous, chromium picolinate and vitamin B12, typically is verifiedaccording to USP standards. The density and pH of the composition andthe level of microbes, e.g., yeast, mold, E. coli and Salmonella, alsotypically are verified according to USP standards. The amount of fattyacids can be verified according to AOAC standards, for example, by gaschromatography (GC), gas liquid chromatography (GLC) or other fatty acidprofiling methods. The levels of heavy metals, such as lead and arsenic,are tested using inductively coupled plasma mass spectrometry (ICP-MS),or by sending a sample of the composition for testing to a testingfacility, such as Eurofins U.S. (Des Moines, Iowa) or Advanced BotanicalConsulting & Testing, Inc. (Tustin, Calif.), or any other facilitycapable of performing such tests. Additionally, Fourier transforminfrared spectroscopy (FTIR) typically is used to obtain a fingerprintof the product, to verify that no other compounds except the desiredingredients are present in the product.

After evaluation, purification, and/or addition of all the ingredients,the product, e.g., emulsion or dry powder, can be packaged, for example,into large containers for storage or into smaller containers foradministration, such as bottles or ampoules (as described below). Theproducts can be transferred to the packaging containers using a transferdevice, such as the transfer device described herein, including transferpumps and fittings as described above or by manual transfer. Forexample, the product can be packaged for storage in containers, such astotes, e.g., 275 gallon totes (such as the 275 gallon bottle with areconditioned CageTote tank IBC, Item No. REN275; Qualsery Enterprises,Inc. (www.qualservcontainer.com)), by transferring the mixture using afood grade hose (Sani-Tech® STHT-R-HD braid-reinforced heavy dutysilicone hose; Sani-Tech West). After transfer, the tote can be closedand sealed, e.g., tied, such as with a cable tie.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

F. Examples

Example 1

A. Method of Producing TPGS Compositions

d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS 1000) wassynthesized from vitamin E succinate according to the following generalprocedure. See also, U.S. patent application Ser. No. 14/207,310 andInternational Patent Application No. PCT/US14/25006.

Polyethylene glycol (PEG) 1000 (168.7 kg) was added to a reaction flaskcontaining 1430 L of toluene, followed by the addition of 71.5 kg ofvitamin E (α-tocopheryl acid) succinate and 2.86 kg of p-toluenesulfonic acid. The reaction mixture was heated to 110-112° C. andrefluxed for up to 6.5 hours, removing the water formed during theesterification reaction by azeotropic distillation. The reaction wasterminated when the desired amounts of TPGS monomer and TPGS dimer wereformed, as indicated by high performance liquid chromatography (HPLC)and thin layer chromatography (TLC), resulting in the TPGS compositionsset forth in Table 1a below. Each TPGS composition in Table 1a wasformed by terminating the reaction at a different time point, up to 6.5hours, and contained various amounts of TPGS monomer and TPGS dimer. Theremainder of the TPGS composition was made up of unreacted startingmaterials, such as vitamin E and PEG The reaction was terminated bycooling the reaction mixture to room temperature, followed by washingwith 25 L of a 10% solution of NaHCO₃. The solution stirred for 10minutes, and after stirring was allowed to separate into layers. Theorganic (toluene) layer was removed, 6 kg of activated carbon (charcoal)was added, and the solution was heated to 55-60° C. and maintained atthis temperature for 1 hour. The solution was then cooled to roomtemperature, filtered through 10 kg of Celite® Hyflo® filter aid (SigmaAldrich, St. Louis, Mo.) and then washed with 100 L of toluene. Thefiltered toluene solution was concentrated by vacuum distillation below60° C. to remove the toluene. Water (140 L) was added to remove tracesof toluene and was then removed via vacuum distillation below 60° C. toobtain ˜180 kg of a crude α-tocopheryl polyethylene glycol 1000succinate composition that contained a mixture of TPGS monomer and TPGSdimer, along with unreacted PEG 1000 and α-tocopherol.

TABLE 1a Amounts of TPGS monomer and TPGS dimer formed during reactionTPGS Monomer Dimer Total composition (%) (%) (% monomer + % dimer) 143.90 53.90 97.80 2 42.80 48.80 91.60 3 40.95 53.15 94.10 4 43.52 49.8093.32 5 55.88 29.27 85.15 6 52.92 33.70 86.62 7 42.76 51.10 93.86 840.39 54.90 95.29 9 57.70 40.40 98.10 10 39.35 35.56 74.91 11 60.0038.10 98.10

A series of extractions were performed on the crude TPGS composition.The crude TPGS composition (˜180 kg) was dissolved in 360 L of methanoland then 540 L of cyclohexane was added. The solution was stirred andthen allowed to separate into layers. The cyclohexane layer was removedand an additional 540 L of cyclohexane was added to the remainingmethanol layer. The solution was stirred and then allowed to separateinto layers. The cyclohexane layer was again removed and an additional540 L of cyclohexane was added to the remaining methanol layer. Thesolution was again stirred and allowed to separate into layers. Thecyclohexane layer was removed, and the remaining methanol layer wasfurther diluted with an additional 270 L of methanol. Activated carbon(18 kg) was added and the solution was heated to 55-60° C. andmaintained at this temperature for 1 hour. The solution was then cooledto room temperature, filtered through 30 kg of Celite® Hyflo® filteraid, and washed with 100 L of methanol. The methanol solution was passedthrough a micron filter, then concentrated via vacuum distillation below60° C. to obtain ˜98-102 kg of a TPGS composition. All traces of solventwere then removed by purging with nitrogen at 55° C. for two hours toobtain ˜98-102 kg of a purified TPGS composition that contained TPGSmonomer and TPGS dimer.

One typical batch of TPGS prepared to contain a high dimerconcentration, and used in the Examples below, had the followingcomponents:

TPGS monomer: 48%

TPGS dimer: 51%

Vitamin E: 0.42%

Vitamin E succinate: 0.46%.

Other typical batches contained:

TPGS monomer: 46.09%-43.15% w/w

TPGS dimer: 39.07%-50.28% w/w

Other: up to about 3%-3.2% w/w

For example, the batches used in Example 11, below, contained:

TPGS monomer: 46.55%-48.72% w/w

TPGS dimer: 46.88%-47.33% w/w

Other: up to about 3.95%-6.55% w/w

B. Evaluation of the Clarity of the TPGS-Containing Compositions by aTurbidity Analysis

The clarity of the TPGS compositions prepared above was evaluated by aturbidity analysis. TPGS compositions 1-11 were formulated as 1 gconcentrates and each were dissolved in 8 oz. of water. The resultingaqueous liquid dilution compositions then were evaluated for clarity bymeasuring turbidity using a nephelometer. Results of the evaluation areset forth in Table 1b below.

Each of the eleven TPGS compositions listed in Table 1a above wasdiluted in water (purified according to the provided methods) using thefollowing steps.

Eight ounces of water was heated in a Pyrex® beaker by placing thebeaker on a Thermolyne hot plate (Model #846925) until the water reached49.8° C. The TPGS composition concentrate was then added to the heatedwater and stirred with a stir rod until dispersed. The resulting aqueousTPGS composition was cooled to room temperature (about 25° C.). Thecooled aqueous TPGS composition was added to an amber-glass screw-topvial (Alcon) for evaluation.

The vials containing the aqueous TPGS compositions were sent to ACZLaboratories, Inc. (Steamboat Springs, Colo.) for turbidity analysisusing a nephelometer. Results are listed in the form of NephelometricTurbidity Units (NTU) and are indicated in Table 1b below.

TABLE 1b Turbidity (NTU) of aqueous TPGS compositions Total TPGS MonomerDimer (% monomer + Turbidity composition (%) (%) % dimer) (NTU) 1 43.9053.90 97.80 8 2 42.80 48.80 91.60 8.2 3 40.95 53.15 94.10 10 4 43.5249.80 93.32 10 5 55.88 29.27 85.15 14 6 52.92 33.70 86.62 14 7 42.7651.10 93.86 18.5 8 40.39 54.90 95.29 39.4 9 57.70 40.40 98.10 71 1039.35 35.56 74.91 80 11 60.00 38.10 98.10 80

Example 2 Preparation of Pre-Emulsion Concentrates Containing TPGS andNon-Polar Ingredients

Pre-emulsion concentrates were prepared according to the methoddescribed below with the ingredients detailed in Tables 2-18. Thepre-emulsion concentrates contained between 31.5% and 97.43% by weight(of the concentrate) of one or more non-polar ingredients and TPGS(α-tocopheryl polyethylene glycol succinate) or benzyl alcohol, or TPGSand benzyl alcohol. The TPGS was prepared as described in Example 1,above.

The pre-emulsion concentrates contained as much as about 97% non-polaringredients that are or contain non-polar compounds. The remainder wasTPGS or benzyl alcohol, or TPGS and benzyl alcohol. Non-polaringredients included: a fish oil that contains 50% of the non-polarcompounds DHA/EPA (sold as VivoMega 3322 TG by GC Rieber Oils,Kristiansund, Norway); an algal oil that contains 40% of the non-polarcompound DHA (sold by GC Rieber Oils, Kristiansund, Norway); an algaloil that contains 35% of the non-polar compound DHA and contains 350 mgDHA/g oil (life's DHA™ S35-O300, sold by DSM Nutritional Products Inc.,Kaiseraugst, Switzerland); a conjugated linoleic acid (CLA) thatcontains 79.6% CLA (Clarinol® G-80, sold by Stepan Lipid Nutrition,Maywood, N.J.); a medium chain triglyceride (MCT) oil that contains 98%MCT (sold by Abitec, Janesville, Wis. and Stepan Lipid Nutrition,Maywood, N.J.); a flaxseed oil that contains 50% C:18-3 alpha-linolenicacid (ALA) (sold by San Mark Ltd., Greensboro, N.C.); resveratrol (soldby Maxsun Industries Inc., Walnut, Calif.); vinpocetine (sold by CyvexNutrition, Irvine, Calif.); sesamin (sold by KEB Nutraceutical USA,Inc., Minneapolis, Minn.); a turmeric/curcumin composition that contains95% curcumin (sold by Siddharth International, Mumbai, India); aphosphatidylserine (PS) composition that contains 40% phosphatidylserineand lesser amounts of phosphatidylinositol and phosphatidylethanolamine(sold by Doosan Corporation and distributed by Perrimondo LLC); vitaminE acetate that contains 1360 IU tocopheryl/g vitamin E oil (sold by DSMNutritional Products Inc., Kaiseraugst, Switzerland); alpha-lipoic acid(sold by Pure Assay Ingredients, Walnut, Calif.); quercetin (sold byPure Assay Ingredients, Walnut, Calif.); pyrroloquinoline quinone (PQQ;Nascent Health Sciences, Allentown, N.J.); and mixtures thereof.Ingredients marked with a “*” were added in overage to ensure the statedamount of non-polar ingredient was in the final product.

Each of the pre-emulsion concentrates set forth in Tables 2-18, below,were prepared using a bench-top process. Larger amounts of thepre-emulsion concentrates can be made by scaling up the bench-topprocess or using a scaled-up manufacturing process, for example, to makelarger batch sizes of the pre-emulsion concentrates. Accordingly, eachof the pre-emulsion concentrates in Tables 2-18 also can be made withthe provided methods as described and a scaled-up process. Furtherdetails for each pre-emulsion concentrate are provided in eachindividual Table.

The bench-top process for making the pre-emulsion concentrates wasperformed using the following general steps. For each of thepre-emulsion concentrates set forth in Tables 2-18, below, the indicatedamount of each ingredient was weighed using a Toledo Scale (ModelGD13x/USA), Sartorius Basic Analytical Scale (Model BA110S) or an OHAUSScale (Model CS2000). Selection of scale depended on the weight of eachingredient being weighed.

The initial ingredients (all ingredients except the non-polaringredients) were added in the indicated amounts (g/batch) to a vessel(a Pyrex® beaker), and mixed with a standard mixer (IKA® model No. RE-16S1, an overhead mixer (laboratory stirrer) compatible with the bench-topprocess). While mixing, the ingredients were heated by a Thermolyne hotplate (Model # SP46615) to reach a temperature of between 60° C. and 70°C.

After the initial ingredients dissolved, e.g., formed a homogeneousmixture, and reached the desired temperature, e.g., 60° C., thenon-polar ingredients were added. The ingredients then were homogenizedby placing a reversible homogenizer (Arde Barinco, Inc.; Model CJ-4E) inthe vessel (beaker) and turning on at 850-1200 RPM. Mixing with thehomogenizer was continued while maintaining the temperature using thehot plate. The baffle plate on the homogenizer was adjusted to achieveand maintain an emulsion, for example, by moving the baffle platefurther into and/or out of the ingredient mixture. Homogenizationcontinued at between 60° C. and 70° C. until the mixture becamehomogeneous. For the preparation of some pre-emulsion concentrates, anadditional solvent, such as ethanol, tetrahydrofuran or hexanes, wasadded to aid in dissolving the non-polar ingredients. The additionalsolvent was then evaporated before further use of the solid phasecomposition.

Unless otherwise indicated, when the ingredients include a surfactant, apreservative and one or more non-polar ingredients, these ingredientswere added sequentially, in the following order: 1) surfactant; 2)preservative; 3) non-polar ingredient. When the ingredients include asurfactant, a preservative, a solvent and one or more non-polaringredients, these ingredients were added sequentially, in the followingorder: 1) surfactant; 2) preservative; 3) solvent; 4) non-polaringredient. The ingredients were heated with the hot plate until thetemperature reached between 60° C. and 70° C. A temperature probe (Model# DPP400W, Cooper-Atkins) was used to measure the temperature of themixing ingredients.

The composition then was filtered, through a 100 micron end-productfilter, and packaged (transferred) by filling into one or more storagecontainers, for example, plastic bottles or 5 gallon pails, where it wascooled to room temperature (about 25° C.). Alternatively, thecomposition was packaged into a bag-in-a-box-type storage container.Depending on the particular ingredients, the resulting concentrateseither were a solid to semi-solid composition at room-temperature(having a waxy consistency) or remained as a liquid.

TABLE 2 Pre-emulsion concentrate containing fish oil (50% DHA/EPA) andTPGS wt % of Ingredient composition Fish oil (50% DHA/EPA blend)* 39.50(non-polar ingredient) TPGS 60.50 Total 100.00

TABLE 3 Pre-emulsion concentrate containing algal oil (40% DHA) and TPGSwt % of Ingredient composition Algal oil (40% DHA) 84.00 (non-polaringredient) TPGS 16.00 Total 100.00

TABLE 4 Pre-emulsion concentrate containing algal oil (35% DHA) and TPGSwt % of Ingredient composition Algal oil (35% DHA) 97.35 (non-polaringredient) TPGS 2.65 Total 100.00

TABLE 5 Pre-emulsion concentrate containing CLA oil (79.6% CLA) and TPGSwt % of Ingredient composition CLA oil (79.6% CLA) 97.43 (non-polaringredient) TPGS 2.57 Total 100.00

TABLE 6 Pre-emulsion concentrate containing MCT oil (98% MCT) and TPGSwt % of Ingredient composition MCT oil (98% MCT) 97.42 (non-polaringredient) TPGS 2.58 Total 100.00

TABLE 7 Pre-emulsion concentrate containing resveratrol and TPGS wt % ofIngredient composition Resveratrol 35.00 (non-polar ingredient) TPGS65.00 Total 100.00

TABLE 8 Pre-emulsion concentrate containing vinpocetine and TPGS wt % ofIngredient composition Vinpocetine 35.00 (non-polar ingredient) TPGS65.00 Total 100.00

TABLE 9 Pre-emulsion concentrate containing sesamin and TPGS wt % ofIngredient composition Sesamin 35.00 (non-polar ingredient) TPGS 65.00Total 100

TABLE 10 Pre-emulsion concentrate containing turmeric/curcumin (95%curcumin) and TPGS wt % of Ingredient composition Turmeric/curcumin (95%curcumin) 31.50 (non-polar ingredient) TPGS 68.50 Total 100.00

TABLE 11 Pre-emulsion concentrate containing turmeric/curcumin (95%curcumin) and TPGS wt % of Ingredient composition Turmeric/curcumin (95%curcumin) 37.10 (non-polar ingredient) TPGS 62.90 Total 100.00

TABLE 12 Pre-emulsion concentrate containing phosphatidylserine (40%Phosphatidylserine) and TPGS wt % of Ingredient compositionPhosphatidylserine (40% PS) 68.40 (non-polar ingredient) TPGS 31.60Total 100.00

TABLE 13 Pre-emulsion concentrate containing phosphatidylserine (40%phosphatidylserine), MCT oil (98% MCT) and TPGS wt % of Ingredientcomposition Phosphatidylserine (40% PS) 68.50 (non-polar ingredient) MCToil (98% MCT) 17.80 (non-polar ingredient) TPGS 13.70 Total 100.00

TABLE 14 Pre-emulsion concentrate containing vitamin E acetate, TPGS,and benzyl alcohol wt % of Ingredient composition Vitamin E acetate(1360 IU tocopheryl/g oil) 95.43 (non-polar ingredient) TPGS 4.07 Benzylalcohol 0.50 (preservative) Total 100.00

TABLE 15 Pre-emulsion concentrate containing alpha- lipoic acid, TPGSand benzyl alcohol wt % of Ingredient composition Alpha-lipoic acid70.00 (non-polar ingredient) TPGS 20.00 Benzyl alcohol 10.00(preservative) Total 100.00

TABLE 16 Pre-emulsion concentrate containing quercetin, TPGS, and benzylalcohol wt % of Ingredient composition Quercetin 35.00 (non-polaringredient) TPGS 64.50 Benzyl alcohol 0.50 (preservative) Total 100.00

TABLE 17 Pre-emulsion concentrate containing PQQ, TPGS, and benzylalcohol wt % of Ingredient composition PQQ 35.00 (non-polar ingredient)TPGS 64.50 Benzyl alcohol 0.50 (preservative) Total 100.00

TABLE 18 Pre-emulsion concentrate containing fish oil (50% DHA/EPA),flaxseed oil (50% ALA), TPGS, and benzyl alcohol wt % of Ingredientcomposition Flaxseed oil (50% ALA) 79.02 (non-polar ingredient) Fish oil(50% DHA/EPA) 0.40 (non-polar ingredient) TPGS 20.08 Benzyl alcohol 0.50(preservative) Total 100.00

Example 3 Preparation of Pre-Spray Emulsions Containing TPGS andNon-Polar Ingredients

The pre-emulsion concentrates of Tables 2-18 were used to preparepre-spray emulsions. The pre-spray emulsions were prepared by combininga pre-emulsion concentrate with the ingredients detailed in Tables19-39, below, according to the general procedure described below. Theresulting pre-spray emulsions contained between 5.25% and 19.49% byweight non-polar ingredient(s) that is or contains non-polar compounds,as shown in Table 40, below.

The ingredients in the pre-spray emulsions included: a pre-emulsionconcentrate prepared as described above in Example 2 (see Tables 2-18);an emulsion stabilizer that is blend of xanthan gum, guar gum and sodiumalginate, sold under the product name SALADIZER®, available from TICGums, Inc. (Belcamp, Md.); a binder, maltodextrin (Archer DanielsMidland Company, Decatur, Ill.); a sucrose fatty acid ester (SFAE) soldunder the trade name DK Ester® (produced by Dai-Ichi Kogyo Seiyaku Co.,Ltd of Japan) in place of some or all of the maltodextrin; citric acid,a pH adjuster; stabilizers, including vitamin C (Pure Assay Ingredients,Walnut, Calif.), potassium bicarbonate (Armand Products, Princeton,N.J.), a green tea extract that contains 40% EGCG (epigallocatechingallate) (Guilin Layn Natural Ingredients Corp., Guilin, China); one ormore co-emulsifiers such as fish collagen (Norland Products Inc.,Cranbury Township, N.J.), a whey protein isolate (Marquez BrothersInternational, Hanford, Calif.), and saponin from quillaja bark (sold byDesert King and Sigma Aldrich, St. Louis, Mo.); and a polar solvent,water, which was purified city water, purified as described below.Before adding to the appropriate phase, as described below, the correctamount of each ingredient (as indicated in Tables 19-39) was weighed outusing either a Sartorius Basic Analytical Scale (Model BA110S), an OHAUSScale (Model CS2000) or a Toledo Scale (Model GD13x/USA). Liquidingredients were weighed in containers, while dry ingredients wereweighed in bags.

Production of the Water Phase

The water phase was prepared in a 1500 mL Pyrex beaker. The appropriateamount of city water was purified by passing the water through thefollowing purifiers, sequentially, in the following order: a carbonfilter, an ion exchange purifier, a reverse osmosis purifier and a 100micron end-point filter. The water (amount indicated in Tables 19-39,below) finally was passed through a UV sterilizer before it was measuredand added to the beaker. The switch controlling the pump and UVsterilizer was then turned off.

The beaker containing the water was placed onto a Thermolyne hot plate(Model No. SP46615). An Arde Barinco reversible homogenizer (Model No.CJ-4E; Arde Barinco, Inc., Norwood, N.J.) was immersed in the water andturned on, using the “forward” setting, at a speed of 30 rpm. The waterphase then was heated to between 60° C. and 70° C. using the Thermolynehot plate while slowly mixing at 30 rpm. The Arde Barinco mixer then wasraised and switched to the “reverse” setting to create a vortex.

The indicated amount of the “water phase” ingredients were added to thewater phase beaker at 60-70° C. When a stabilizer was present, such asKHCO₃, the ingredients were added in the following order: 1) emulsionstabilizer; 2) co-emulsifier; 3) co-surfactant(s); and 4) stabilizer(s).Mixing was continued at 60-70° C. until the emulsion stabilizer wasmostly dispersed in the water phase and until the water phase was readyto be combined with the solid phase. Temperatures were measured with apH and temperature meter (Hanna Instruments, Model No. HI 8314).

Combining the Water and Oil Phases

Once the water phase had been prepared and was at 60-70° C., the ArdeBarinco homogenizer was turned on the “forward” setting at 30 rpm in thewater phase beaker and the oil phase (i.e., pre-emulsion concentrate)was transferred to the water phase beaker. Mixing with the homogenizerat 30 rpm continued until the phases had combined.

The ingredients were mixed and cooled in a water bath until the mixturereached 50° C. The indicated amount of pH adjuster was then added andthe mixture was continuously mixed at 30 rpm using the Arde Barincomixer on “forward” and further cooled to 30° C. Additional water wasadded to account for any evaporation that had occurred during theprocess. Temperatures and pH were measured with a temperature and pHmeter (Hanna Instruments, Model No. HI 8314). The pH of each mixture wasmeasured to confirm that it was around 2.76.

Tables 19-39, below, indicate the amount (g) of each ingredient perbatch of the pre-spray emulsion, the phase each ingredient was added,and the percentage by weight (wt %) of each ingredient.

TABLE 19 Pre-spray emulsion containing fish oil (50% DHA/EPA) and TPGSwt % of Ingredient g/batch Phase composition Water 284.37 Water 56.87(polar solvent) KHCO₃ 23.06974 Water 4.61 (stabilizer) Maltodextrin54.507268 Water 10.90 (binder/carrier) SFAE 41.3388 Water 8.27(co-surfactant) SALADIZER ® emulsifier 0.33 Water 0.07 (emulsionstabilizer) Vitamin C 10.00 Water 2.00 (stabilizer) Saponin 3.03 Water0.61 (co-emulsifier) Pre-emulsion concentrate 83.34 Oil 16.67 containingfish oil (50% DHA/EPA) and TPGS (Table 2 above) Totals 500.00 100.00

TABLE 20 Pre-spray emulsion containing algal oil (40% DHA) and TPGS wt %of Ingredient g/batch Phase composition Water 284.37 Water 56.87 (polarsolvent) KHCO₃ 23.06974 Water 4.61 (stabilizer) Maltodextrin 46.172823Water 9.24 (binder/carrier) SFAE 33.0044 Water 6.60 (co-surfactant)SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer) Vitamin C 10.00 Water2.00 (stabilizer) Saponin 3.03 Water 0.61 (co-emulsifier) Pre-emulsionconcentrate 100.01 Oil 20.00 containing algal oil (40% DHA) and TPGS(Table 3 above) Totals 500.00 100.00

TABLE 21 Pre-spray emulsion containing algal oil (35% DHA) and TPGS wt %of Ingredient g/batch Phase composition Water 284.37 Water 56.87 (polarsolvent) KHCO₃ 16.66889 Water 3.33 (stabilizer) Green tea extract (40%EGCG) 44.239232 Water 8.85 (stabilizer) SFAE 41.3388 Water 8.27(co-surfactant) SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer)Vitamin C 10.00 Water 2.00 (stabilizer) Saponin 3.03 Water 0.61(co-emulsifier) Pre-emulsion concentrate 100.01 Oil 20.00 containingalgal oil (35% DHA) and TPGS (Table 4 above) Totals 500.00 100.00

TABLE 22 Pre-spray emulsion containing CLA oil (79.6% CLA) and TPGS wt %of Ingredient g/batch Phase composition Water 170.62 Water 56.87 (polarsolvent) KHCO₃ 10.00133 Water 3.33 (stabilizer) Fish collagen 26.543539Water 8.85 (binder) SFAE 24.8033 Water 8.27 (co-surfactant) SALADIZER ®0.20 Water 0.07 (emulsion stabilizer) Vitamin C 6.00 Water 2.00(stabilizer) Saponin 1.82 Water 0.61 (co-emulsifier) Pre-emulsionconcentrate 60.01 Oil 20.00 containing CLA oil (79.6% CLA) and TPGS(Table 5 above) Totals 300.00 100.00

TABLE 23 Pre-spray emulsion containing CLA oil (79.6% CLA) and TPGS wt %of Ingredient g/batch Phase composition Water 86.23 Water 57.48 (polarsolvent) KHCO₃ 5.00 Water 3.33 (stabilizer) Whey protein 13.27 Water8.85 (co-emulsifier) SFAE 12.40 Water 8.27 (co-surfactant) SALADIZER ®0.10 Water 0.07 (emulsion stabilizer) Vitamin C 3.00 Water 2.00(stabilizer) Pre-emulsion concentrate 30.00 Oil 20.00 containing CLA oil(79.6% CLA) and TPGS (Table 5 above) Totals 150.00 100.00

TABLE 24 Pre-spray emulsion containing MCT oil (98% MCT) and TPGS wt %of Ingredient g/batch Phase composition Water 568.74 Water 56.87 (polarsolvent) KHCO₃ 33.33778 Water 3.33 (stabilizer) Green tea extract (40%EGCG) 88.478464 Water 8.85 (stabilizer) SFAE 82.6777 Water 8.27(co-surfactant) SALADIZER ® 0.67 Water 0.07 (emulsion stabilizer)Vitamin C 20.00 Water 2.00 (stabilizer) Saponin 6.07 Water 0.61(co-emulsifier) Pre-emulsion concentrate 200.03 Oil 20.00 containing MCToil (98% MCT) and TPGS (Table 6 above) Totals 1000.00 100.00

TABLE 25 Pre-spray emulsion containing MCT oil (98% MCT) and TPGS wt %of Ingredient g/batch Phase composition Water 170.62 Water 56.87 (polarsolvent) KHCO₃ 10.00133 Water 3.33 (stabilizer) Fish collagen 26.543539Water 8.85 (binder) SFAE 24.8033 Water 8.27 (co-surfactant) SALADIZER ®0.20 Water 0.07 (emulsion stabilizer) Vitamin C 6.00 Water 2.00(stabilizer) Saponin 1.82 Water 0.61 (co-emulsifier) Pre-emulsionconcentrate 60.01 Oil 20.00 containing MCT oil (98% MCT) and TPGS (Table6 above) Totals 300.00 100.00

TABLE 26 Pre-spray emulsion containing MCT oil (98% MCT) and TPGS wt %of Ingredient g/batch Phase composition Water 170.62 Water 56.87 (polarsolvent) KHCO₃ 10.00133 Water 3.33 (stabilizer) Whey protein 26.543539Water 8.85 (co-emulsifier) SFAE 24.8033 Water 8.27 (co-surfactant)SALADIZER ® 0.20 Water 0.07 (emulsion stabilizer) Vitamin C 6.00 Water2.00 (stabilizer) Saponin 1.82 Water 0.61 (co-emulsifier) Pre-emulsionconcentrate 60.01 Oil 20.00 containing MCT oil (98% MCT) and TPGS (Table6 above) Totals 300.00 100.00

TABLE 27 Pre-spray emulsion containing MCT oil (98% MCT) and TPGS wt %of Ingredient g/batch Phase composition Water 1437.166 Water 57.48(polar solvent) KHCO₃ 83.333 Water 3.33 (stabilizer) Whey protein221.166 Water 8.85 (co-emulsifier) SFAE 206.666 Water 8.27(co-surfactant) SALADIZER ® 1.666 Water 0.07 (emulsion stabilizer)Vitamin C 50.00 Water 2.00 (stabilizer) Pre-emulsion concentrate 500.00Oil 20.00 containing MCT oil (98% MCT) and TPGS (Table 6 above) Totals2500.00 100.00

TABLE 28 Pre-spray emulsion containing resveratrol and TPGS wt % ofIngredient g/batch Phase composition Water 284.37 Water 56.87 (polarsolvent) KHCO₃ 23.06974 Water 4.61 (stabilizer) Maltodextrin 64.508601Water 12.90 (binder/carrier) SFAE 41.3388 Water 8.27 (co-surfactant)SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer) Saponin 3.03 Water0.61 (co-emulsifier) Pre-emulsion concentrate 83.34 Oil 16.67 containingresveratrol and TPGS (Table 7 above) Totals 500.00 100.00

TABLE 29 Pre-spray emulsion containing vinpocetine and TPGS wt % ofIngredient g/batch Phase composition Water 284.37 Water 56.87 (polarsolvent) KHCO₃ 23.06974 Water 4.61 (stabilizer) Maltodextrin 64.508601Water 12.90 (binder/carrier) SFAE 41.3388 Water 8.27 (co-surfactant)SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer) Saponin 3.03 Water0.61 (co-emulsifier) Pre-emulsion concentrate 83.34 Oil 16.67 containingvinpocetine and TPGS (Table 8 above) Totals 500.00 100.00

TABLE 30 Pre-spray emulsion containing sesamin and TPGS wt % ofIngredient g/batch Phase composition Water 284.37 Water 56.87 (polarsolvent) KHCO₃ 23.06974 Water 4.61 (stabilizer) Maltodextrin 64.508601Water 12.90 (binder/carrier) SFAE 41.3388 Water 8.27 (co-surfactant)SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer) Saponin 3.03 Water0.61 (co-emulsifier) Pre-emulsion concentrate 83.34 Oil 16.67 containingsesamin and TPGS (Table 9 above) Totals 500.00 100.00

TABLE 31 Pre-spray emulsion containing turmeric/curcumin (95% curcumin)and TPGS wt % of Ingredient g/batch Phase composition Water 284.37 Water56.87 (polar solvent) KHCO₃ 23.06974 Water 4.61 (stabilizer)Maltodextrin 64.508601 Water 12.90 (binder/carrier) SFAE 41.3388 Water8.27 (co-surfactant) SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer)Saponin 3.03 Water 0.61 (co-emulsifier) Pre-emulsion concentrate 83.34Oil 16.67 containing turmeric/curcumin (95% curcumin) and TPGS (Table 10above) Totals 500.00 100.00

TABLE 32 Pre-spray emulsion containing turmeric/curcumin (95% curcumin)and TPGS wt % of Ingredient g/batch Phase composition Water 284.37 Water56.87 (polar solvent) KHCO₃ 23.06974 Water 4.61 (stabilizer)Maltodextrin 64.508601 Water 12.90 (binder/carrier) SFAE 41.3388 Water8.27 (co-surfactant) SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer)Saponin 3.03 Water 0.61 (co-emulsifier) Pre-emulsion concentrate 83.34Oil 16.67 containing turmeric/curcumin (95% curcumin) and TPGS (Table 11above) Totals 500.00 100.00

TABLE 33 Pre-spray emulsion containing phosphatidylserine (40%phosphatidyl serine) and TPGS wt % of Ingredient g/batch Phasecomposition Water 284.37 Water 56.87 (polar solvent) KHCO₃ 23.06974Water 4.61 (stabilizer) Maltodextrin 64.508601 Water 12.90(binder/carrier) SFAE 41.3388 Water 8.27 (co-surfactant) SALADIZER ®0.33 Water 0.07 (emulsion stabilizer) Saponin 3.03 Water 0.61(co-emulsifier) Pre-emulsion concentrate 83.34 Oil 16.67 containingphosphatidylserine (40% phosphatidylserine) and TPGS (Table 12 above)Totals 500.00 100.00

TABLE 34 Pre-spray emulsion containing phosphatidylserine (40%phosphatidylserine), MCT oil (98% MCT), and TPGS wt % of Ingredientg/batch Phase composition Water 170.62 Water 56.87 (polar solvent) KHCO₃13.84 Water 4.61 (stabilizer) Maltodextrin 38.71 Water 12.90(binder/carrier) SFAE 24.80 Water 8.27 (co-surfactant) SALADIZER ® 0.20Water 0.07 (emulsion stabilizer) Saponin 1.82 Water 0.61 (co-emulsifier)Pre-emulsion concentrate 50.01 Oil 16.67 containing phosphatidylserine(40% phosphatidylserine), MCT oil (98% MCT), and TPGS (Table 13 above)Totals 300.00 100.00

TABLE 35 Pre-spray emulsion containing vitamin E acetate, TPGS, andbenzyl alcohol wt % of Ingredient g/batch Phase composition Water 85.31Water 56.87 (polar solvent) Maltodextrin 23.273103 Water 15.51(binder/carrier) SFAE 12.4017 Water 8.27 (co-surfactant) SALADIZER ®0.10 Water 0.07 (emulsion stabilizer) Vitamin C 3.00 Water 2.00(stabilizer) Saponin 0.91 Water 0.61 (co-emulsifier) Pre-emulsionconcentrate 25.00 Oil 16.67 containing vitamin E acetate, TPGS, andbenzyl alcohol (Table 14 above) Totals 150.00 100.00

TABLE 36 Pre-spray emulsion containing alpha- lipoic acid, TPGS, andbenzyl alcohol wt % of Ingredient g/batch Phase composition Water 284.33Water 56.86 (polar solvent) KHCO₃ 23.06667 Water 4.61 (stabilizer)Maltodextrin 87.900 Water 17.58 (binder/carrier) SFAE 41.3333 Water 8.27(co-surfactant) SALADIZER ® 0.33 Water 0.07 (emulsion stabilizer)Vitamin C 10.00 Water 2.00 (stabilizer) Saponin 3.03 Water 0.61(co-emulsifier) Pre-emulsion concentrate 50.00 Oil 10.00 containingalpha-lipoic acid, TPGS, and benzyl alcohol (Table 15 above) Totals500.00 100.000

TABLE 37 Pre-spray emulsion containing quercetin, TPGS, and benzylalcohol wt % of Ingredient g/batch Phase composition Water 170.60 Water56.86 (polar solvent) Citric acid 0.4000 Water 0.13 (pH adjuster)Maltodextrin 54.20 Water 18.07 (binder/carrier) SFAE 24.80 Water 8.27(co-surfactant) Pre-emulsion concentrate 50.00 Oil 16.67 containingquercetin, TPGS, and benzyl alcohol (Table 16 above) Totals 300.00100.00

TABLE 38 Pre-spray emulsion containing PQQ, TPGS, and benzyl alcohol wt% of Ingredient g/batch Phase composition Water 85.3 Water 56.86 (polarsolvent) Citric acid 0.20 Water 0.13 (pH adjuster) Maltodextrin 27.1Water 18.07 (binder/carrier) SFAE 12.400 Water 8.27 (co-surfactant)Pre-emulsion concentrate containing PQQ, TPGS, 25.0 Oil 16.67 and benzylalcohol (Table 17 above) Totals 150.00 100.00

TABLE 39 Pre-spray emulsion containing fish oil (50% DHA/EPA), flaxseedoil (50% ALA), TPGS, and benzyl alcohol wt % of Ingredient g/batch Phasecomposition Water 284.37 Water 56.87 (polar solvent) KHCO₃ 23.06974Water 4.61 (stabilizer) Maltodextrin 54.507268 Water 10.90(binder/carrier) SFAE 41.3388 Water 8.27 (co-surfactant) SALADIZER ®0.33 Water 0.07 (emulsion stabilizer) Vitamin C 10.00 Water 2.00(stabilizer) Saponin 3.03 Water 0.61 (co-emulsifier) Pre-emulsionconcentrate 83.34 Oil 16.67 containing fish oil (50% DHA/EPA), flaxseedoil (50% ALA), TPGS, and benzyl alcohol (Table 18 above) Totals 500.00100.00

The pre-spray emulsions of Tables 18-36, above, contained between 5.25%and 19.49% by weight non-polar ingredient(s), as shown in Table 37,below.

TABLE 40 Amount of non-polar ingredient(s) in pre-spray emulsions wt %of pre-emulsion wt % of non-polar concentrate in ingredient in Non-polaringredient pre-spray emulsion pre-spray emulsion Fish oil 16.67 6.58(Table 19 above) Algal oil 20.00 16.80 (Table 20 above) Algal oil 20.0019.47 (Table 21 above) CLA oil 20.00 19.49 (Table 22 above) CLA oil20.00 19.49 (Table 23 above) MCT oil 20.00 19.48 (Table 24 above) MCToil 20.00 19.48 (Table 25 above) MCT oil 20.00 19.48 (Table 26 above)MCT oil 20.00 19.48 (Table 27 above) Resveratrol 16.67 5.83 (Table 28above) Vinpocetine 16.67 5.83 (Table 29 above) Sesamin 16.67 5.83 (Table30 above) Turmeric/curcumin 16.67 5.25 (Table 31 above)Turmeric/curcumin 16.67 6.18 (Table 32 above) Phosphatidylserine 16.6711.40 (Table 33 above) Phosphatidylserine/ 16.67 14.39 MCT oil (Table 34above) Vitamin E acetate 16.67 15.91 (Table 35 above) Alpha-lipoic acid10.00 7.00 (Table 36 above) Quercetin 16.67 5.83 (Table 37 above) PQQ16.67 5.83 (Table 38 above) Fish oil/flaxseed oil 16.67 13.24 (Table 39above)

Example 4 Preparation of Dry Powders Containing TPGS and Non-PolarIngredients

The pre-spray emulsions described above in Example 3 and indicated inTables 19-39 were then spray dried into dry powders. The final drypowders contained between 12.18% and 45.83% non-polar ingredient, assummarized in Table 62 below, and were prepared according to thefollowing procedure. Tables 41-61 below indicate the percentage byweight (wt %) of each ingredient per batch of the final dry powder afterspray drying the pre-spray emulsions.

The dry powders were prepared using a standard spray dryer equipped witha rotary atomizer nozzle or a standard spray nozzle. Alternatively, afluid bed dryer can be used. A pre-spray emulsion was added to a tankand mixed with a mixer when necessary to keep the liquid homogenousduring the spray drying process. The liquid was then pumped to the topof the spray dryer (GEA Niro, Denmark) and sprayed through a nozzleatomizer into the spray dryer, typically kept at a temperature of 180°C. When the spray dryer was equipped with a fluid bed, the liquid wassprayed through a rotary atomizer at lower temperatures into the spraydryer. Water then evaporated and pooled at the top of the dryer, whilethe powder collected at the floor bottom of the dryer, where it wasrecovered. After recovering the powder, some powders were rewet orinstantized by redissolving the dry power in water at a 1:3 or 1:1powder to water ratio (e.g., 30-50 g of powder was dissolved in 100 g ofwater) and spray drying a second time. The powders then weresifted/filtered using a 60-80 micron mesh screen.

Some pre-spray emulsions required the addition of extra water (i.e.,evaporation water) as a processing aid to make the emulsion thinner andable to pass through the dryer pump more easily. The extra water wasadded to the pre-spray emulsion at 35° C. and was evaporated during thespray dry process, along with the rest of the water in the pre-sprayemulsion.

TABLE 41 Dry powder containing fish oil (50% DHA/EPA) and TPGS wt % ofIngredient composition KHCO₃ 10.62 (stabilizer) Maltodextrin 25.85(binder/carrier) SFAE 19.02 (co-surfactant) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.60 (stabilizer) Saponin 1.40 (co-emulsifier)Pre-emulsion concentrate containing 38.36 fish oil (50% DHA/EPA) andTPGS (Table 2 above) Total 100.00

TABLE 42 Dry powder containing algal oil (40% DHA) and TPGS wt % ofIngredient composition KHCO₃ 10.70 (stabilizer) Maltodextrin 21.41(binder/carrier) SFAE 15.31 (co-surfactant) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate containing 46.38 algal oil (40% DHA) and TPGS(Table 3 above) Total 100.00

TABLE 43 Dry powder containing algal oil (35% DHA) and TPGS wt % ofIngredient composition KHCO₃ 7.73 (stabilizer) Green tea extract (40%EGCG) 20.52 (stabilizer) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15(emulsion stabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41(co-emulsifier) Pre-emulsion concentrate containing 46.38 algal oil (35%DHA) and TPGS (Table 4 above) Total 100.00

TABLE 44 Dry powder containing CLA oil (79.6% CLA) and TPGS wt % ofIngredient composition KHCO₃ 7.73 (stabilizer) Fish collagen 20.52(binder) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate containing 46.38 CLA oil (79.6% CLA) and TPGS(Table 5 above) Total 100.00

TABLE 45 Dry powder containing CLA oil (79.6% CLA) and TPGS wt % ofIngredient composition KHCO₃ 7.85 (stabilizer) Whey protein 20.81(co-emulsifier) SFAE 19.44 (co-surfactant) SALADIZER ® 0.16 (emulsionstabilizer) Vitamin C 4.70 (stabilizer) Pre-emulsion concentratecontaining 47.04 CLA oil (79.6% CLA) and TPGS (Table 5 above) Total100.00

TABLE 46 Dry powder containing MCT oil (98% MCT) and TPGS wt % ofIngredient composition KHCO₃ 7.73 (stabilizer) Green tea extract (40%EGCG) 20.52 (stabilizer) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15(emulsion stabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41(co-emulsifier) Pre-emulsion concentrate containing 46.38 MCT oil (98%MCT) and TPGS (Table 6 above) Total 100.00

TABLE 47 Dry powder containing MCT oil (98% MCT) and TPGS wt % ofIngredient composition KHCO₃ 7.73 (stabilizer) Fish collagen 20.52(stabilizer) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate containing 46.38 MCT oil (98% MCT) and TPGS(Table 6 above) Total 100.00

TABLE 48 Dry powder containing MCT oil (98% MCT) and TPGS wt % ofIngredient composition KHCO₃ 7.73 (stabilizer) Whey protein 20.52(co-emulsifier) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate containing 46.38 MCT oil (98% MCT) and TPGS(Table 6 above) Total 100.00

TABLE 49 Dry powder containing MCT oil (98% MCT) and TPGS wt % ofIngredient composition KHCO₃ 7.84 (stabilizer) Whey protein 20.81(co-emulsifier) SFAE 19.45 (co-surfactant) SALADIZER ® 0.16 (emulsionstabilizer) Vitamin C 4.70 (stabilizer) Pre-emulsion concentratecontaining 47.04 MCT oil (98% MCT) and TPGS (Table 6 above) Total 100.00

TABLE 50 Dry powder containing resveratrol and TPGS wt % of Ingredientcomposition KHCO₃ 10.70 (stabilizer) Maltodextrin 29.92 (binder/carrier)SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsion stabilizer)Saponin 1.41 (co-emulsifier) Pre-emulsion concentrate containing 38.65resveratrol and TPGS (Table 7 above) Total 100.00

TABLE 51 Dry powder containing vinpocetine and TPGS wt % of Ingredientcomposition KHCO₃ 10.70 (stabilizer) Maltodextrin 29.92 (binder/carrier)SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsion stabilizer)Saponin 1.41 (co-emulsifier) Pre-emulsion concentrate containing 38.65vinpocetine and TPGS (Table 8 above) Total 100.00

TABLE 52 Dry powder containing sesamin and TPGS wt % of Ingredientcomposition KHCO₃ 10.70 (stabilizer) Maltodextrin 29.92 (binder/carrier)SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsion stabilizer)Saponin 1.41 (co-emulsifier) Pre-emulsion concentrate containing 38.65sesamin and TPGS (Table 9 above) Total 100.00

TABLE 53 Dry powder containing turmeric/curcumin (95% curcumin) and TPGSwt % of Ingredient composition KHCO₃ 10.70 (stabilizer) Maltodextrin29.92 (binder/carrier) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15(emulsion stabilizer) Saponin 1.41 (co-emulsifier) Pre-emulsionconcentrate containing 38.65 turmeric/curcumin (95% curcumin) and TPGS(Table 10 above) Total 100.00

TABLE 54 Dry powder containing turmeric/curcumin (95% curcumin) and TPGSwt % of Ingredient composition KHCO₃ 10.70 (stabilizer) Maltodextrin29.92 (binder/carrier) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15(emulsion stabilizer) Saponin 1.41 (co-emulsifier) Pre-emulsionconcentrate containing 38.65 turmeric/curcumin (95% curcumin) and TPGS(Table 11 above) Total 100.00

TABLE 55 Dry powder containing phosphatidylserine (40% phosphatidylserine) and TPGS wt % of Ingredient composition KHCO₃ 10.70 (stabilizer)Maltodextrin 29.92 (binder/carrier) SFAE 19.17 (co-surfactant)SALADIZER ® 0.15 (emulsion stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate containing 38.65 phosphatidylserine (40% PS)and TPGS (Table 12 above) Total 100.00

TABLE 56 Dry powder containing phosphatidylserine (40%phosphatidylserine), MCT oil (98% MCT), and TPGS wt % of Ingredientcomposition KHCO₃ 10.70 (stabilizer) Maltodextrin 29.92 (binder/carrier)SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsion stabilizer)Saponin 1.41 (co-emulsifier) Pre-emulsion concentrate containingphosphatidylserine 38.65 (40% PS), MCT oil (98% MCT) and TPGS (Table 13above) Total 100.00

TABLE 57 Dry powder containing vitamin E acetate, TPGS, and benzylalcohol wt % of Ingredient composition Maltodextrin 35.98(binder/carrier) SFAE 19.17 (co-surfactant) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate containing 38.65 vitamin E acetate, TPGS, andbenzyl alcohol (Table 14 above) Total 100.00

TABLE 58 Dry powder containing alpha-lipoic acid, TPGS, and benzylalcohol wt % of Ingredient composition KHCO₃ 10.70 (stabilizer)Maltodextrin 40.76 (binder/carrier) SFAE 19.17 (co-surfactant)SALADIZER ® 0.15 (emulsion stabilizer) Vitamin C 4.64 (stabilizer)Saponin 1.41 (co-emulsifier) Pre-emulsion concentrate containing 23.18alpha-lipoic acid, TPGS, and benzyl alcohol (Table 15 above) Total100.00

TABLE 59 Dry powder containing quercetin, TPGS, and benzyl alcohol wt %of Ingredient composition Citric acid 0.31 (pH adjuster) Maltodextrin41.89 (binder/carrier) SFAE 19.17 (co-surfactant) Pre-emulsionconcentrate containing 38.64 quercetin, TPGS, and benzyl alcohol (Table16 above) Total 100.00

TABLE 60 Dry powder containing PQQ, TPGS, and benzyl alcohol wt % ofIngredient composition Citric acid 0.31 (pH adjuster) Maltodextrin 41.89(binder/carrier) SFAE 19.17 (co-surfactant) Pre-emulsion concentratecontaining 38.64 PQQ, TPGS, and benzyl alcohol (Table 17 above) Total100.00

TABLE 61 Dry powder containing fish oil (50% DHA/EPA), flaxseed oil (50%ALA), TPGS, and benzyl alcohol wt % of Ingredient composition KHCO₃10.62 (stabilizer) Maltodextrin 25.85 (binder/carrier) SFAE 19.02(co-surfactant) SALADIZER ® 0.15 (emulsion stabilizer) Vitamin C 4.60(stabilizer) Saponin 1.40 (co-emulsifier) Pre-emulsion concentratecontaining fish oil (50% 38.36 DHA/EPA), flaxseed oil (50% ALA), TPGS,and benzyl alcohol (Table 18 above) Total 100.00

The dry powders depicted above in Tables 41-61 that contained thepre-emulsion concentrates described in Example 2 contained between12.18% and 45.83% by weight non-polar ingredient(s), as shown in Table62, below.

TABLE 62 Amount of non-polar ingredient(s) in dry powders wt % ofpre-emulsion wt % of non-polar concentrate in dry ingredient in dryNon-polar ingredient powder powder Fish oil 38.36 15.15 (Table 41 above)Algal oil 46.38 38.96 (Table 42 above) Algal oil 46.38 45.15 (Table 43above) CLA oil 46.38 45.19 (Table 44 above) CLA oil 47.04 45.83 (Table45 above) MCT oil 46.38 45.18 (Table 46 above) MCT oil 46.38 45.18(Table 47 above) MCT oil 46.38 45.18 (Table 48 above) MCT oil 47.0445.83 (Table 49 above) Resveratrol 38.65 13.53 (Table 50 above)Vinpocetine 38.65 13.53 (Table 51 above) Sesamin 38.65 13.53 (Table 52above) Turmeric/curcumin 38.65 12.18 (Table 53 above) Turmeric/curcumin38.65 14.34 (Table 54 above) Phosphatidylserine 38.65 26.44 (Table 55above) Phosphatidylserine/MCT 38.65 33.35 oil (Table 56 above) Vitamin Eacetate 38.65 36.88 (Table 57 above) Alpha-lipoic acid 23.18 16.23(Table 58 above) Quercetin 38.64 13.52 (Table 59 above) PQQ 38.64 13.52(Table 60 above) Fish oil/flaxseed oil 38.36 30.46 (Table 61 above)

Example 5 Preparation of Another Dry Powder Containing Non-PolarIngredients

A. Preparation of the Pre-Emulsion Concentrate

A pre-emulsion concentrate was prepared according to the methoddescribed above in Example 2 using the ingredients detailed in Table 63,below. The pre-emulsion concentrate contained benzyl alcohol, a naturalpreservative, and 99.5% by weight (of the concentrate) of fish oil, anon-polar ingredient which contains 50% of the non-polar compoundDHA/EPA (sold as VivoMega 3322 TG by GC Rieber Oils, Kristiansund,Norway).

The pre-emulsion concentrate set forth in Table 63, below, was madeusing a bench-top process according to the provided methods (see Example2). The pre-emulsion concentrate can alternatively be made by scaling upthe bench-top process, using a scaled-up manufacturing process of theprovided methods, for example, to make larger batch sizes of thepre-emulsion concentrate.

TABLE 63 Pre-emulsion concentrate containing fish oil (50% DHA/EPA) andbenzyl alcohol wt % of Ingredient composition Benzyl alcohol 0.5 Fishoil (50% DHA/EPA blend)* 99.5 (non-polar ingredient) Total 100.00

B. Preparation of the Pre-Spray Emulsion

The pre-emulsion concentrate described above and shown in Table 63 wasused in the preparation of a pre-spray emulsion. The pre-spray emulsionwas prepared by combining the pre-emulsion concentrate that contained99.5% of the non-polar ingredient fish oil (50% DHA/EPA blend),described in Table 63, above, with the ingredients detailed in Table 64,below, according to the general procedure described above in Example 3.The resulting pre-spray emulsion thus contained 16.669% by weightpre-emulsion concentrate containing 99.5% of the non-polar ingredientfish oil (i.e., the resulting pre-spray emulsion contained a total of16.59% by weight non-polar ingredient).

The ingredients in the pre-spray emulsion included the pre-emulsionconcentrate containing the non-polar ingredient fish oil, prepared asdescribed above (see Table 63); a surfactant, a sucrose fatty acid ester(SFAE; sold under the trade name DK Ester®, produced by Dai-Ichi KogyoSeiyaku Co., Ltd of Japan); an emulsion stabilizer that was a blend ofxanthan gum, guar gum and sodium alginate, sold under the product nameSALADIZER®, available from TIC Gums, Inc. (Belcamp, Md.); the bindermaltodextrin (sold by Archer Daniels Midland Company, Decatur, Ill.);stabilizers, including vitamin C (sold by Pure Assay Ingredients,Walnut, Calif.) and potassium bicarbonate; a co-emulsifier that wassaponin from quillaja bark (sold by Desert King, San Diego, Calif., andSigma Aldrich, St. Louis, Mo.); and a polar solvent, water, which waspurified city water, purified as described above (see Example 3). Beforeadding to the appropriate phase, as described above, the correct amountof each ingredient (as indicated in Table 64) was weighed out usingeither a Sartorius Basic Analytical Scale (Model BA110S), an OHAUS Scale(Model CS2000) or a Toledo Scale (Model GD13x/USA). Liquid ingredientswere weighed in containers, while dry ingredients were weighed in bags.

Table 64, below, indicates the amount (g) of each ingredient per batchof the pre-spray emulsion, the phase each ingredient was added, and thepercentage by weight (wt %) of each ingredient.

TABLE 64 Pre-spray emulsion containing fish oil (50% DHA/EPA), benzylalcohol, and SFAE wt % of Ingredient g/batch Phase composition Water284.37 Water 56.874 (polar solvent) KHCO₃ 23.06974 Water 4.614(stabilizer) Maltodextrin 54.507268 Water 10.901 (binder/carrier) SFAE41.3388 Water 8.268 (co-surfactant) SALADIZER ® 0.33 Water 0.067emulsifier (emulsion stabilizer) Vitamin C 10.00 Water 2.000(stabilizer) Saponin 3.03 Water 0.607 (co-emulsifier) Pre-emulsionconcentrate 83.34 Oil 16.669 containing fish oil (50% DHA/EPA) andbenzyl alcohol (Table 63 above) Totals 500.00 100.000

C. Preparation of the Dry Powder

The pre-spray emulsion described above and indicated in Table 64 wasthen spray dried into a dry powder according to the procedure detailedin Example 4. The addition of extra water (i.e., evaporation water) tothe pre-spray emulsion was required as a processing aid to make theemulsion thinner and able to pass through the dryer pump more easily.The extra water was added to the pre-spray emulsion at 35° C. and wasevaporated during the spray dry process, along with the rest of thewater in the pre-spray emulsion.

The final dry powder contained 38.36% of the pre-emulsion concentratecontaining 99.5% fish oil (i.e., 38.17% non-polar ingredient). Table 65,below, indicates the percentage by weight (wt %) of each ingredient perbatch of the final dry powder after spray drying the pre-spray emulsion.

TABLE 65 Dry powder containing fish oil (50% DHA/EPA), benzyl alcohol,and SFAE wt % of Ingredient composition KHCO₃ 10.62 (stabilizer)Maltodextrin 25.85 (binder/carrier) SFAE 19.02 (co-surfactant)SALADIZER ® 0.15 (emulsion stabilizer) Vitamin C 4.60 (stabilizer)Saponin 1.40 (co-emulsifier) Pre-emulsion concentrate 38.36 containingfish oil (50% DHA/EPA) and benzyl alcohol (Table 63 above) Total 100.00The final dry powder thus contained 38.17% of the non-polar ingredientfish oil.

Example 6 Comparison Example of Preparation of Dry Powders ContainingNon-Polar Ingredients and No Sucrose Fatty Acid Ester

This example is provided to show that addition of a sucrose (or othersugar) fatty acid ester in place of maltodextrin or other such binder ina pre-spray emulsion permits production of powders with a higherconcentration of non-polar ingredients. In order to produce powders forspray drying, it is necessary to include a threshold amount of solidsfor forming the powder. To achieve this, the TPGS is reduced in amount,and SFAE is added in its place. In the absence of the added SFAE, theemulsions, and particularly the emulsions with higher amounts ofnon-polar ingredient, when dried, do not form dry free-flowing powders,but are sludge-like and oily and have too high a moisture content.

A series of pre-emulsion concentrates containing increasingconcentrations of non-polar ingredient, as set forth in Tables 66-69,were prepared and used to prepare pre-spray emulsions that contained abinder (maltodextrin), but no SFAE. Preparation of dry powders from eachpre-spray emulsion was attempted. If successful, the resulting drypowders would have contained 5.5%, 11.62%, 27.5% and 45.18% non-polaringredient. As shown below, it was possible to produce dry powders thatcontained less than about 15% (5.5%, 11.62%) non-polar ingredient, butit was not possible to produce dry powders from the pre-spray emulsionscontaining the pre-emulsion concentrates with the highest amount ofnon-polar ingredients, and powders with the lower amounts (between about15%-30%) exhibited undesirable properties. A dry powder could not beproduced from the pre-spray emulsion with the highest concentration ofnon-polar ingredient (45.18%) and no SFAE. For all concentrations ofnon-polar ingredients, the presence of SFAE in place of a binder, suchas maltodextrin, in the pre-spray emulsions improved the properties ofthe resulting powders, and permitted preparation of powders with veryhigh concentrations (above 30%, 35%, or 40%) of non-polar ingredients.

A. Preparation of the Pre-Emulsion Concentrates

Pre-emulsion concentrates were prepared according to the bench-topprocess described in Example 2, above, with the ingredients detailed inTables 66-69, below. The pre-emulsion concentrates contained between16.84% and 97.42% by weight (of the concentrate) of a non-polaringredient, with the remainder of the concentrate containing TPGS orTPGS and benzyl alcohol. The non-polar compounds included a conjugatedlinoleic acid (CLA) that contains 70% CLA (Clarinol® CLA, sold by StepanLipid Nutrition, Maywood, N.J.); a coenzyme Q10 (coQ10) compound thatcontains greater than 98% ubidicarenone (ubiquinone), sold under thename Kaneka Q10™ (USP Ubidicarenone; Kaneka Nutrients, L.P., Pasadena,Tex.); and an algal oil that contains 35% of the non-polar compound DHAand contains 350 mg DHA/g oil (life's DHA™ S35-O300, sold by DSMNutritional Products Inc., Kaiseraugst, Switzerland).

TABLE 66 Pre-emulsion concentrate containing coQ10, TPGS, and benzylalcohol wt % of Ingredient composition TPGS 82.66 Benzyl alcohol 0.50(preservative) CoQ10 16.84 (non-polar ingredient) Total 100.00

TABLE 67 Pre-emulsion concentrate containing coQ10, TPGS, and benzylalcohol wt % of Ingredient composition TPGS 65.82 Benzyl alcohol 0.50(preservative) CoQ10 33.68 (non-polar ingredient) Total 100.00

TABLE 68 Pre-emulsion concentrate containing CLA oil (70% CLA) and TPGSwt % of Ingredient composition TPGS 16.58 CLA oil (70% CLA) 83.42(non-polar ingredient) Total 100.00

TABLE 69 Pre-emulsion concentrate containing algal oil (35% DHA) andTPGS wt % of Ingredient composition TPGS 2.58 Algal oil (35% DHA) 97.42(non-polar ingredient) Total 100.00

B. Preparation of the Pre-Spray Emulsions

Pre-spray emulsions were prepared from the pre-emulsion concentrates ofTables 66-69, above, by combining the pre-emulsion concentrate with theingredients detailed in Tables 70-73, below, according to the generalprocedure described above in Example 3. The pre-spray emulsionscontained between about 14.21% and 20.003% of a pre-emulsionconcentrate, resulting in pre-spray emulsions that contained between2.39% and 19.48% non-polar ingredient. None of the pre-spray emulsionscontained SFAE.

In addition to the pre-emulsion concentrates prepared as described above(see Tables 66-69), the pre-spray emulsions also contained: maltodextrin(sold by Archer Daniels Midland Company, Decatur, Ill.); the emulsionstabilizer SALADIZER® (TIC Gums, Inc.; Belcamp, Md.); stabilizers,including vitamin C (Pure Assay Ingredients, Walnut, Calif.), potassiumbicarbonate (Armand Products, Princeton, N.J.), and a green tea extractthat contains 40% EGCG (epigallocatechin gallate) (Guilin Layn NaturalIngredients Corp., Guilin, China); a co-emulsifier, saponin fromquillaja bark (sold by Desert King and Sigma Aldrich, St. Louis, Mo.);citric acid, a pH adjuster; and a polar solvent, water, which waspurified city water, purified as described above.

Before adding to the appropriate phase, as described above in Example 2,the correct amount of each ingredient (as indicated in Tables 70-73) wasweighed out using either a Sartorius Basic Analytical Scale (ModelBA110S), an OHAUS Scale (Model CS2000) or a Toledo Scale (ModelGD13x/USA). Liquid ingredients were weighed in containers, while dryingredients were weighed in bags.

Tables 70-73 set forth the ingredients included in each pre-sprayemulsion, the amount (g) of each ingredient per batch of the pre-sprayemulsion, the phase to which each ingredient was added, and thepercentage by weight (wt %) of each ingredient.

TABLE 70 Pre-spray emulsion containing coQ10, TPGS, and benzyl alcoholand maltodextrin in place of SFAE wt % of Ingredient g/batch Phasecomposition Water 23051.31282 Water 56.86 (polar solvent) Citric acid54.05 Water 0.13 (pH adjuster) Maltodextrin 11578.4 Water 28.56(binder/carrier) SALADIZER ® 96.4750 Water 0.24 (emulsion stabilizer)Pre-emulsion concentrate 5761.5 Oil 14.21 containing coQ10, TPGS, andbenzyl alcohol (Table 66 above) Totals 40541.67 100.000

TABLE 71 Pre-spray emulsion containing coQ10, TPGS, and benzyl alcoholand maltodextrin in place of SFAE wt % of Ingredient g/batch Phasecomposition Water 23051.31282 Water 56.86 (polar solvent) Citric acid54.05 Water 0.13 (pH adjuster) Maltodextrin 11578.4 Water 28.56(binder/carrier) SALADIZER ® 96.4750 Water 0.24 (emulsion stabilizer)Pre-emulsion concentrate 5761.5 Oil 14.21 containing coQ10, TPGS, andbenzyl alcohol (Table 67 above) Totals 40541.67 100.000

TABLE 72 Pre-spray emulsion containing CLA oil (70% CLA) and TPGS andmaltodextrin in place of SFAE wt % of Ingredient g/batch Phasecomposition Water 284.38 Water 56.876 (polar solvent) Citric acid 0.6668Water 0.133 (pH adjuster) Maltodextrin 142.69 Water 28.538(binder/carrier) SALADIZER ® 1.18 Water 0.237 (emulsion stabilizer)Pre-emulsion concentrate 71.08 Oil 14.216 containing CLA oil (70% CLA)and TPGS (Table 68 above) Totals 500.00 100.000

TABLE 73 Pre-spray emulsion containing algal oil (35% DHA) and TPGS andmaltodextrin in place of SFAE wt % of Ingredient g/batch Phasecomposition Water 284.3712 Water 56.874 (polar solvent) KHCO₃ 16.6689Water 3.334 (stabilizer) Green tea extract (40% EGCG) 44.2392 Water8.848 (stabilizer) Maltodextrin 41.3388 Water 8.268 (binder/carrier)SALADIZER ® 0.333378 Water 0.067 (emulsion stabilizer) Vitamin C 10.001Water 2.000 (stabilizer) Saponin 3.03373 Water 0.607 (co-emulsifier)Pre-emulsion concentrate 100.0134 Oil 20.003 containing algal oil (35%DHA) and TPGS (Table 69 above) Totals 500.00 100.000

C. Attempted Preparation of Dry Powders

Preparation of a dry powder was attempted from each of the pre-sprayemulsions that contained a binder (maltodextrin) in place of sucrosefatty acid esters (described above and in Tables 70-73) according to theprocedure detailed in Example 4, above. The final compositions containedbetween 32.94% and 46.38% of a pre-emulsion concentrate, resulting infinal compositions that contained between 5.5% and 45.18% non-polaringredient. A dry powder was not formed from the composition thatcontained the highest amount of non-polar ingredient (45.18%) and noSFAE (see Table 77). Dry powders were formed from the compositionscontaining lower amounts of non-polar ingredient (see Tables 74-76).

Tables 74-77, below, indicate the percentage by weight (wt %) of eachingredient per batch of the composition after attempting to spray drythe pre-spray emulsion.

TABLE 74 Dry powder containing coQ10, TPGS, and benzyl alcohol andmaltodextrin in place of SFAE wt % of Ingredient composition Citric acid0.31 (pH adjuster) Maltodextrin 66.20 (binder/carrier) SALADIZER ® 0.55(emulsion stabilizer) Pre-emulsion concentrate containing 32.94 coQ10,TPGS, and benzyl alcohol (Table 66 above) Total 100.00

TABLE 75 Dry powder containing coQ10, TPGS, and benzyl alcohol andmaltodextrin in place of SFAE wt % of Ingredient composition Citric acid0.31 (pH adjuster) Maltodextrin 64.66 (binder/carrier) SALADIZER ® 0.55(emulsion stabilizer) Pre-emulsion concentrate containing 34.49 coQ10,TPGS, and benzyl alcohol (Table 67 above) Total 100.00

TABLE 76 Dry powder containing CLA oil (70% CLA) and TPGS andmaltodextrin in place of SFAE wt % of Ingredient composition Citric acid0.31 (pH adjuster) Maltodextrin 66.18 (binder/carrier) SALADIZER ® 0.55(emulsion stabilizer) Pre-emulsion concentrate containing 32.96 CLA oil(70% CLA) and TPGS (Table 68 above) Total 100.00

TABLE 77 Attempted dry powder containing algal oil (35% DHA) and TPGSand maltodextrin in place of SFAE wt % of Ingredient composition KHCO₃7.73 (stabilizer) Green tea extract (40% EGCG) 20.52 (stabilizer)Maltodextrin 19.17 (binder/carrier) SALADIZER ® 0.15 (emulsionstabilizer) Vitamin C 4.64 (stabilizer) Saponin 1.41 (co-emulsifier)Pre-emulsion concentrate 46.38 containing algal oil (35% DHA) and TPGS(Table 69 above) Total 100.00

Example 7 Preparation and Comparison of Dry Powders Containing Non-PolarIngredients and TPGS with and without Sucrose Fatty Acid Esters

Two dry powders were prepared from pre-spray emulsions that eachcontained a pre-emulsion concentrate containing the non-polar ingredientfish oil (50% DHA/EPA blend), TPGS and benzyl alcohol. One powdercontained the binder maltodextrin, while the other containedmaltodextrin and SFAE in place of some of the maltodextrin.

Table 78, below, lists the ingredients used in each pre-emulsionconcentrate, prepared according to the general procedure described inExample 2, above. The pre-emulsion concentrates contained either 40.025%(Composition 12A) or 79.42% (Composition 13A) of the non-polaringredient fish oil that contains 50% of the non-polar compounds DHA/EPA(sold as VivoMega 3322 TG by GC Rieber Oils, Kristiansund, Norway).

TABLE 78 Preparation of two pre-emulsion concentrates containing fishoil (50% DHA/EPA) and TPGS wt % of wt % of Ingredient Composition 12AComposition 13A TPGS 59.475 20.08 Benzyl alcohol 0.50 0.50(preservative) Fish oil (50% DHA/EPA) 40.025 79.42 (non-polaringredient) Total 100.00 100.00

Compositions 12A and 13A (Table 78) were used to prepare pre-sprayemulsions 12B and 13B, respectively, with the ingredients detailed inTable 79, below, according to the general procedure described above inExample 3. Composition 12B, which contained maltodextrin and no SFAE,contained 14.21% of the pre-emulsion concentrate 12A containing 40.025%fish oil (i.e., 5.69% non-polar ingredient). Composition 13B, whichcontained SFAE in place of some of the maltodextrin, contained 16.67% ofthe pre-emulsion concentrate 13A containing 79.42% fish oil (i.e.,13.24% non-polar ingredient).

TABLE 79 Pre-spray emulsions containing fish oil (50% DHA/EPA) and TPGS,with and without SFAE wt % of wt % of Ingredient Composition 12BComposition 13B Water 56.86 56.87 (polar solvent) Citric acid 0.13 — (pHadjuster) Maltodextrin 28.80 10.90 (binder/carrier) KHCO₃ — 4.61(stabilizer) SFAE — 8.27 (co-surfactant) SALADIZER ® — 0.07 (emulsionstabilizer) Vitamin C — 2.00 (stabilizer) Saponin — 0.61 (co-emulsifier)Pre-emulsion concentrate 14.21 16.67 containing fish oil (50% DHA/EPA)and TPGS (Table 78 above) Total 100.00 100.00

The pre-spray emulsions described above in Table 79 (Compositions 12Band 13B) were then spray dried into dry powders 12C and 13C,respectively, according to the general procedure described above inExample 4. Final dry powder 12C, which contained maltodextrin and noSFAE, contained 32.94% of the pre-emulsion concentrate 12A containing40.025% fish oil (i.e., 13.18% non-polar ingredient). Composition 13C,which contained SFAE in place of some of the maltodextrin, contained38.36% of the pre-emulsion concentrate 13A containing 79.42% fish oil(i.e., 30.47% non-polar ingredient). Table 80, below, indicates thepercentage by weight (wt %) of each ingredient per batch of the finaldry powders after spray drying the pre-spray emulsions.

TABLE 80 Dry powders containing fish oil (50% DHA/EPA), with and withoutSFAE wt % of wt % of Ingredient Composition 12C Composition 13C Citricacid 0.31 — (pH adjuster) Maltodextrin 66.75 25.85 (binder/carrier)KHCO₃ — 10.62 (stabilizer) SFAE — 19.02 (co-surfactant) SALADIZER ® —0.15 (emulsion stabilizer) Vitamin C — 4.60 (stabilizer) Saponin — 1.40(co-emulsifier) Pre-emulsion concentrate 32.94 38.36 containing fish oil(50% DHA/EPA) and TPGS (Table 78 above) Total 100.00 100.00

The composition containing SFAE in place of some of the maltodextrin(Composition 13C) formed a more free-flowing dry powder and was able toincorporate a higher amount of non-polar ingredient (i.e., 30.47% vs.13.18%) than the composition that did not contain SFAE, but containedmaltodextrin (Composition 12C).

Example 8 Preparation and Comparison of Dry Powders Containing Non-PolarIngredients and TPGS with and without Sucrose Fatty Acid Esters

This example is provided to show that addition of a sucrose (or othersugar) fatty acid ester in place of maltodextrin or other such binder ina pre-spray emulsion permits production of powders with a higherconcentration of non-polar ingredients. Pre-emulsion concentrates wereprepared containing non-polar ingredients, TPGS, and sucrose fatty acidester. Pre-spray emulsions that contained SFAE were prepared from thepre-emulsion concentrates. Comparative pre-emulsion concentrates wereused to prepare comparative pre-spray emulsions in which the sucrosefatty acid ester was omitted. Preparation of dry powders from each wasattempted. Dry powders could not be produced from the compositionscontaining maltodextrin in place of sucrose fatty acid ester (i.e.,compositions not containing any sucrose fatty acid ester). Thus, thepresence of SFAE in place of a binder, such as maltodextrin, in thepre-spray emulsions improves the properties of the resulting powders,and permits preparation of powders with high concentrations (above 30%,35%, or 40%) of non-polar ingredients.

A. Preparation of the Pre-Emulsion Concentrates

Pre-emulsion concentrates were prepared according to the bench-topprocess described above in Example 2, with the ingredients detailed inTables 81-84 below. The pre-emulsion concentrates contained a non-polaringredient, with the remainder of the concentrate containing TPGS orTPGS and benzyl alcohol. The non-polar ingredients included a conjugatedlinoleic acid (CLA) that contains 70% CLA (Clarinol® CLA, sold by StepanLipid Nutrition, Maywood, N.J.); a medium chain triglyceride (MCT) oilthat contains 98% MCT (sold by Abitec, Janesville, Wis. and Stepan LipidNutrition, Maywood, N.J.); pyrroloquinoline quinone (PQQ; Nascent HealthSciences, Allentown, N.J.); and an algal oil that contains 35% of thenon-polar compound DHA and contains 350 mg DHA/g oil (life'sDHA™S35-O300, sold by DSM Nutritional Products Inc., Kaiseraugst,Switzerland).

TABLE 81 Preparation of two pre-emulsion concentrates containing algaloil (35% DHA) and TPGS wt % of wt % of Ingredient Composition 14AComposition 15A TPGS 2.65 2.58 Algal oil (35% DHA) 97.35 97.42(non-polar ingredient) Total 100.00 100.00

TABLE 82 Preparation of two pre-emulsion concentrates containing CLA oil(79.6% CLA) and TPGS wt % of wt % of Ingredient Composition 16AComposition 17A TPGS 2.57 2.58 CLA oil (79.6% CLA) 97.43 97.42(non-polar ingredient) Total 100.00 100.00

TABLE 83 Preparation of two pre-emulsion concentrates containing MCT oil(98% MCT) and TPGS wt % of wt % of Ingredient Composition 18AComposition 19A TPGS 2.58 2.58 MCT oil (98% MCT) 97.42 97.42 (non-polaringredient) Total 100.00 100.00

TABLE 84 Preparation of two pre-emulsion concentrates containing PQQ andTPGS wt % of wt % of Ingredient Composition 20A Composition 21A TPGS64.50 69.50 Benzyl alcohol 0.50 0.50 (preservative) PQQ 35.00 30.00(non-polar ingredient) Total 100.00 100.00

B. Preparation of the Pre-Spray Emulsions

Pre-spray emulsions were prepared from the pre-emulsion concentrates ofTables 81-84, above, by combining a pre-emulsion concentrate with theingredients detailed in Tables 85-88, below, according to the generalprocedure described above in Example 3. The pre-spray emulsionscontained a pre-emulsion concentrate containing a non-polar ingredientand TPGS, and were formulated either with sucrose fatty acid ester, orwith maltodextrin in place of sucrose fatty acid ester.

In addition to the pre-emulsion concentrates prepared as described above(see Tables 81-84), the pre-spray emulsions also contained: maltodextrin(sold by Archer Daniels Midland Company, Decatur, Ill.); the emulsionstabilizer SALADIZER® (TIC Gums, Inc.; Belcamp, Md.); stabilizers,including vitamin C (Pure Assay Ingredients, Walnut, Calif.), potassiumbicarbonate (Armand Products, Princeton, N.J.), and a green tea extractthat contains 40% EGCG (epigallocatechin gallate) (Guilin Layn NaturalIngredients Corp., Guilin, China); a co-emulsifier, saponin fromquillaja bark (sold by Desert King and Sigma Aldrich, St. Louis, Mo.);citric acid, a pH adjuster; and a polar solvent, water, which waspurified city water, purified as described above.

Before adding to the appropriate phase, as described above in Example 3,the correct amount of each ingredient (as indicated in Tables 85-88) wasweighed out using either a Sartorius Basic Analytical Scale (ModelBA110S), an OHAUS Scale (Model CS2000) or a Toledo Scale (ModelGD13x/USA). Liquid ingredients were weighed in containers, while dryingredients were weighed in bags.

Tables 85-88 set forth the ingredients included in each pre-sprayemulsion, the amount (g) of each ingredient per batch of the pre-sprayemulsion, the phase to which each ingredient was added, and thepercentage by weight (wt %) of each ingredient.

TABLE 85 Pre-spray emulsions containing algal oil (35% DHA), with andwithout SFAE wt % of wt % of Ingredient Composition 14B Composition 15BWater 56.87 56.87 (polar solvent) Maltodextrin — 8.27 (binder/carrier)KHCO₃ 3.33 3.33 (stabilizer) Green tea extract (40% EGCG) 8.85 8.85(stabilizer) SFAE 8.27 — (co-surfactant) SALADIZER ® 0.07 0.07 (emulsionstabilizer) Vitamin C 2.00 2.00 (stabilizer) Saponin 0.61 0.61(co-emulsifier) Pre-emulsion concentrate 20.00 20.00 containing algaloil (35% DHA) and TPGS (Table 81 above) Total 100.00 100.00

TABLE 86 Pre-spray emulsions containing CLA oil (79.6% CLA), with andwithout SFAE wt % of wt % of Ingredient Composition 16B Composition 17BWater 57.48 57.48 (polar solvent) Maltodextrin — 8.27 (binder/carrier)KHCO₃ 3.33 3.33 (stabilizer) Whey protein 8.85 8.85 (co-emulsifier) SFAE8.27 — (co-surfactant) SALADIZER ® 0.07 0.07 (emulsion stabilizer)Vitamin C 2.00 2.00 (stabilizer) Pre-emulsion concentrate 20.00 20.00containing CLA oil (79.6% CLA) and TPGS (Table 82 above) Total 100.00100.00

TABLE 87 Pre-spray emulsions containing MCT oil (98% MCT), with andwithout SFAE wt % of wt % of Ingredient Composition 18B Composition 19BWater 57.48 57.48 (polar solvent) Maltodextrin — 8.27 (binder/carrier)KHCO₃ 3.33 3.33 (stabilizer) Whey protein 8.85 8.85 (co-emulsifier) SFAE8.27 — (co-surfactant) SALADIZER ® 0.07 0.07 (emulsion stabilizer)Vitamin C 2.00 2.00 (stabilizer) Pre-emulsion concentrate 20.00 20.00containing MCT oil (98% MCT) and TPGS (Table 83 above) Total 100.00100.00

TABLE 88 Pre-spray emulsions containing PQQ, with and without SFAE wt %of wt % of Ingredient Composition 20B Composition 21B Water 56.86 58.87(polar solvent) Maltodextrin 18.07 26.33 (binder/carrier) Citric acid0.13 0.13 (pH adjuster) SFAE 8.27 — (co-surfactant) Pre-emulsionconcentrate 16.67 16.67 containing PQQ, benzyl alcohol and TPGS (Table84 above) Total 100.00 100.00

C. Preparation of Dry Powders

Formation of a dry powder from each of the pre-spray emulsions describedabove (Tables 85-88), was attempted, according to the procedure detailedin Example 4, above. Tables 89-92, below, indicate the percentage byweight (wt %) of each ingredient per batch of the final compositionafter spray drying of the pre-spray emulsions was attempted. Duringpreparation of the dry powders, the emulsions were continuously mixed inorder to keep the mixture homogenous. Dry powders were obtained from allof the pre-spray emulsions containing sucrose fatty acid ester(Compositions 14B, 16B, 18B and 20B), but dry powders were not formedwhen maltodextrin was used as a binder in place of sucrose fatty acidester (Compositions 15C, 17C, 19C and 21C). When maltodextrin wasincluded in place of the SFAE, the end compositions were sludge-likematerials, not dry powders. Hence, this Example demonstrates thataddition of SFAE in place of some of the binder, such as maltodextrin,in pre-spray emulsions permits preparation of dry powders containingrather high amounts of non-polar ingredients.

TABLE 89 Dry powders containing algal oil (35% DHA), with and withoutSFAE wt % of wt % of Ingredient Composition 14C Composition 15C KHCO₃7.73 7.73 (stabilizer) Green tea extract (40% EGCG) 20.52 20.52(stabilizer) SFAE 19.17 — (co-surfactant) Maltodextrin — 19.17(binder/carrier) SALADIZER ® 0.15 0.15 (emulsion stabilizer) Vitamin C4.64 4.64 (stabilizer) Saponin 1.41 1.41 (co-emulsifier) Pre-emulsionconcentrate 46.38 46.38 containing algal oil (35% DHA) and TPGS (Table81 above) Total 100.00 100.00

TABLE 90 Dry powders containing CLA oil (79.6% CLA), with and withoutSFAE wt % of wt % of Ingredient Composition 16C Composition 17C KHCO₃7.85 7.85 (stabilizer) Whey protein 20.81 20.81 (co-emulsifier) SFAE19.44 — (co-surfactant) SALADIZER ® 0.16 0.16 (emulsion stabilizer)Maltodextrin — 19.44 (binder/carrier) Vitamin C 4.70 4.70 (stabilizer)Pre-emulsion concentrate 47.04 47.04 containing CLA oil (79.6% CLA) andTPGS (Table 82 above) Total 100.00 100.00

TABLE 91 Dry powders containing MCT oil (98% MCT), with and without SFAEwt % of wt % of Ingredient Composition 18C Composition 19C KHCO₃ 7.847.84 (stabilizer) Whey protein 20.81 20.81 (co-emulsifier) SFAE 19.45 —(co-surfactant) Maltodextrin — 19.45 (binder/carrier) SALADIZER ® 0.160.16 (emulsion stabilizer) Vitamin C 4.70 4.70 (stabilizer) Pre-emulsionconcentrate 47.04 47.04 containing MCT oil (98% MCT) and TPGS (Table 83above) Total 100.00 100.00

TABLE 92 Dry powders containing PQQ, with and without SFAE wt % of wt %of Ingredient Composition 20C Composition 21C Citric acid 0.31 0.31 (pHadjuster) Maltodextrin 41.89 61.06 (binder/carrier) SFAE 19.17 —(co-surfactant) Pre-emulsion concentrate 38.64 38.64 containing PQQ,TPGS, and benzyl alcohol (Table 84 above) Total 100.00 100.00

Example 9 Preparation of Dry Powders Containing TPGS and Non-PolarIngredients

A. Preparation of Pre-Emulsion Concentrates

Pre-emulsion concentrates were prepared according to the methoddescribed above in Example 2 using the ingredients detailed in Tables93-97, below. The pre-emulsion concentrates contained between 37.1% and97.42% by weight (of the concentrate) of one or more non-polaringredients and either TPGS (α-tocopheryl polyethylene glycol succinate)or TPGS and benzyl alcohol. The TPGS was prepared as described inExample 1.

The pre-emulsion concentrates contained as much as about 97% non-polaringredient. The remainder was TPGS or TPGS and benzyl alcohol. Non-polaringredients in the concentrates included fish oils that contain 500 mgof the non-polar compounds DHA/EPA (sold as AlaskOmega® TG300200 M EU byOrganic Technologies, Coshocton, Ohio); a carotenoid-containingcompound, astaxanthin (an oil containing 10% astaxanthin sold asAstaPure® by Alga Technologies, Hevel Eilot, Israel); a dihydrocapsiatecompound naturally found in CH-19 Sweet peppers (sold as CapsiAtra byGlanbia Nutritionals, Carlsbad, Calif.); vitamin K2 that contains 97% ofthe MK-7 form (sold as MenaQ7® by NattoPharma®, Metuchen, N.J.); amedium chain triglyceride (MCT) oil that contains 98% MCT (sold byAbitec, Janesville, Wis. and Stepan Lipid Nutrition, Maywood, N.J.); andcombinations thereof.

The pre-emulsion concentrates set forth in Tables 93-97, below, wereprepared using a bench-top process according to the provided methods(see Example 2). The pre-emulsion concentrates can alternatively be madeby scaling up the bench-top process, using a scaled-up manufacturingprocess of the provided methods, for example, to make larger batch sizesof the pre-emulsion concentrates.

TABLE 93 Pre-emulsion concentrate containing fish oil (60% DHA/EPA) andTPGS wt % of Ingredient composition Fish oil (60% DHA/EPA blend) 97.42(non-polar ingredient) TPGS 2.58 Total 100.00

TABLE 94 Pre-emulsion concentrate containing fish oil (60% DHA/EPA) andTPGS wt % of Ingredient composition Fish oil (60% DHA/EPA blend) 97.42(non-polar ingredient) TPGS 2.58 Total 100.00

TABLE 95 Pre-emulsion concentrate containing astaxanthin (10%astaxanthin) and TPGS wt % of Ingredient composition Astaxanthin (10%)80 (non-polar ingredient) TPGS 20 Total 100.00

TABLE 96 Pre-emulsion concentrate containing dihydrocapsiate and TPGS wt% of Ingredient composition Dihydrocapsiate 37.1 (non-polar ingredient)TPGS 62.9 Total 100.00

TABLE 97 Pre-emulsion concentrate containing MCT oil (98% MCT), vitaminK2 (97% MK-7), benzyl alcohol and TPGS wt % of Ingredient compositionMCT oil (98% MCT) 31.99 (non-polar ingredient) Vitamin K2 (MK-7) 3.99(non-polar ingredient) TPGS 58.0 Benzyl alcohol 6.02 (preservative)Total 100.00

B. Preparation of the Pre-Spray Emulsions

The pre-emulsion concentrates described above and shown in Tables 93-97were used in the preparation of pre-spray emulsions. The pre-sprayemulsions were prepared by combining the pre-emulsion concentrate withthe ingredients detailed in Tables 98-102, below, according to thegeneral procedure described above in Example 3. The resulting pre-sprayemulsions contained between 6.18% and 19.49%, by weight, non-polaringredient.

The ingredients in the pre-spray emulsions included: the pre-emulsionconcentrates containing non-polar ingredients, prepared as describedabove (see Tables 93-97); a surfactant, a sucrose fatty acid ester(SFAE) (sold as DK Ester® by Dai-Ichi Kogyo Seiyaku Co., Ltd, Japan); aco-emulsifier, saponin from quillaja bark (Desert King International,San Diego, Calif.; Sigma Aldrich, St. Louis, Mo.); an emulsionstabilizer that was a blend of xanthan gum, guar gum and sodiumalginate, sold under the product name SALADIZER®, available from TICGums, Inc. (Belcamp, Md.); the binders maltodextrin (sold by ArcherDaniels Midland Company, Decatur, Ill.) and a highly branched cyclicdextrin (HBCD) (sold as Cluster Dextrin® by Glico Nutrition, Japan);stabilizers, including vitamin C (sold by Pure Assay Ingredients,Walnut, Calif.), potassium bicarbonate, and green tea extracts thatcontained 40% or 50% epigallocatechin gallate (EGCG) (Guilin LaynNatural Ingredients, Corp., Guilin, China); sweeteners that includederythritol, stevia (sold as Stevia Leaf Powder Extract, Product codeSTE091, by MiniStar International Inc.), and sorbitol; flavor agentsthat included pink grapefruit, natural mandarin orange (346316), naturalwatermelon (600171), and natural sour yuzu (347528), all sold by GoldCoast Ingredients, Inc. (Commerce, Calif.), natural fresh orange(L-17283), natural blueberry (BL-238), natural watermelon (WM-122), andnatural sour yuzu (L-20609), all sold by Mission Flavors and Fragrances,Inc. (Foothill Ranch, Calif.), natural orange tangerine (DABJ826) andnatural blueberry pomegranate (DABJ831), sold by Wild Flavors (Erlanger,Ky.), and green tea flavor, sold by Kerry, Inc. (Beloit, Wis.); a pHadjuster, citric acid; and a polar solvent, water, which was purifiedcity water, purified as described above (see Example 3). Ingredientsmarked with a * were added in the indicated amount of overage to ensurethe final composition contained the stated amount of this ingredient.

Before adding to the appropriate phase, as described above, the correctamount of each ingredient (as indicated in Tables 98-102) was weighedout using either a Sartorius Basic Analytical Scale (Model BA110S), anOHAUS Scale (Model CS2000) or a Toledo Scale (Model GD13x/USA). Liquidingredients were weighed in containers, while dry ingredients wereweighed in bags.

Tables 98-102, below, indicate the amount (g) of each ingredient perbatch of the pre-spray emulsion, the phase each ingredient was added,and the percentage by weight (wt %) of each ingredient.

TABLE 98 Pre-spray emulsion containing fish oil (50% DHA/EPA) and TPGSwt % of Ingredient g/batch Phase composition Water 268.42 Water 44.74(polar solvent) KHCO₃ 10.99 Water 1.83 (stabilizer) Green tea extract(50% EGCG) 27.50 Water 4.58 (stabilizer) Vitamin C 14.04 Water 2.34(stabilizer) SALADIZER ® emulsifier 0.22 Water 0.04 (emulsionstabilizer) SFAE 10.34 Water 1.72 (co-surfactant) Maltodextrin 49.50Water 8.25 (binder/carrier) Highly branched cyclic dextrin (HBCD) 29.50Water 4.92 (binder/carrier) Erythritol 10.99 Water 1.83 (sweetener)Stevia 15.46 Water 2.58 (sweetener) Pink grapefruit flavor 54.99 Water9.17 (flavor) Natural mandarin orange 2.67 Water 0.45 (flavor) Naturalfresh orange 3.37 Water 0.56 (flavor) Natural blueberry 3.57 Water 0.60(flavor) Natural watermelon 1.20 Water 0.20 (flavor) Natural sour yuzu6.96 Water 1.16 (flavor) Citric acid 7.77 Water 1.29 (pH adjuster)Pre-emulsion concentrate 82.49 Oil 13.75 containing fish oil (50%DHA/EPA) and TPGS (Table 93 above) Totals 600.00 100.00

TABLE 99 Pre-spray emulsion containing fish oil (50% DHA/EPA) and TPGSwt % of Ingredient g/batch Phase composition Water 279.37 Water 55.87(polar solvent) KHCO₃ 16.67 Water 3.33 (stabilizer) Green tea extract(40% EGCG) 44.23 Water 8.85 (stabilizer) Vitamin C 10.00 Water 2.00(stabilizer) SALADIZER ® emulsifier 0.33 Water 0.07 (emulsionstabilizer) SFAE 41.33 Water 8.27 (co-surfactant) Saponin 3.03 Water0.61 (co-emulsifier) Green tea flavor 5.00 Water 1.00 (flavor)Pre-emulsion concentrate 100.01 Oil 20.00 containing fish oil (50%DHA/EPA) and TPGS (Table 94 above) Totals 100.00

TABLE 100 Pre-spray emulsion containing astaxanthin (10% astaxanthin)and TPGS wt % of Ingredient g/batch Phase composition Water 6255.33Water 56.87 (polar solvent) KHCO₃ 507.47 Water 4.61 (stabilizer) VitaminC 220.00 Water 2.00 (stabilizer) SALADIZER ® emulsifier 7.33 Water 0.07(emulsion stabilizer) SFAE 909.33 Water 8.27 (co-surfactant) Saponin26.77 Water 0.24 (co-emulsifier) Highly branched cyclic dextrin (HBCD)1240.43 Water 11.28 (binder/carrier) Pre-emulsion concentrate 1833.33Oil 16.67 containing astaxanthin and TPGS (Table 95 above) Totals 100.00

TABLE 101 Pre-spray emulsion containing dihydrocapsiate and TPGS wt % ofIngredient g/batch Phase composition Water 85.31 Water 56.87 (polarsolvent) SALADIZER ® emulsifier 0.10 Water 0.07 (emulsion stabilizer)SFAE 12.40 Water 8.27 (co-surfactant) Saponin 0.91 Water 0.61(co-emulsifier) Maltodextrin 19.35 Water 12.90 (binder/carrier) Citricacid 6.92 Water 4.61 (pH adjuster) Pre-emulsion concentrate 25.00 Oil16.67 containing dihydrocapsiate and TPGS (Table 96 above) Totals 150.00100.00

TABLE 102 Pre-spray emulsion containing MCT oil (98% MCT), vitamin K2(97% MK-7), benzyl alcohol, and TPGS wt % of Ingredient g/batch Phasecomposition Water 49.47 Water 56.87 (polar solvent) SALADIZER ®emulsifier 0.06 Water 0.07 (emulsion stabilizer) SFAE 3.89 Water 4.47(co-surfactant) Highly branched cyclic dextrin (HBCD) 8.874 Water 10.20(binder/carrier) Sorbitol 1.45 Water 1.67 (sweetener) Pre-emulsionconcentrate 23.26 Oil 26.73 containing MCT oil, vitamin K2 (MK-7),benzyl alcohol and TPGS* (20% overage) (Table 97 above) Totals 87.00100.00

The pre-spray emulsions of tables 98-102, above, contained between 6.18%and 19.49%, by weight, non-polar ingredient(s), as shown in Table 103,below.

TABLE 103 Amount of non-polar ingredient(s) in pre-spray emulsions wt %of pre-emulsion wt % of non-polar concentrate in pre- ingredient in pre-Non-polar ingredient spray emulsion spray emulsion Fish oil 13.75 13.39(Table 98 above) Fish oil 20.00 19.49 (Table 99 above) Astaxanthin 16.6713.33 (Table 100 above) Dihydrocapsiate 16.67 6.18 (Table 101 above) MCToil/vitamin K2 (MK-7) 26.73 9.62 (Table 102 above)

C. Preparation of the Dry Powder

The pre-spray emulsions described above and indicated in Tables 98-102were then spray dried into dry powders according to the proceduredetailed in Example 4. The addition of extra water (i.e., evaporationwater) to the pre-spray emulsions was required as a processing aid tomake the emulsions thinner and able to pass through the dryer pump moreeasily. The extra water was added to the pre-spray emulsions at 35° C.and was evaporated during the spray dry process, along with the rest ofthe water in the pre-spray emulsions.

Tables 104-108, below, indicate the percentage by weight (wt %) of eachingredient per batch of the final dry powders after spray drying thepre-spray emulsions.

TABLE 104 Dry powder containing fish oil (50% DHA/EPA) and TPGS wt % ofIngredient composition KHCO₃ 4.25 (stabilizer) Green tea extract (50%EGCG) 10.62 (stabilizer) Vitamin C 5.42 (stabilizer) SALADIZER ®emulsifier 0.08 (emulsion stabilizer) SFAE 3.99 (co-surfactant)Maltodextrin 19.12 (binder/carrier) Highly branched cyclic dextrin(HBCD) 11.40 (binder/carrier) Erythritol 4.25 (sweetener) Stevia 5.98(sweetener) Citric acid 3.00 (pH adjuster) Pre-emulsion concentrate31.87 containing fish oil (50% DHA/EPA) and TPGS (Table 98 above) Totals100.000

TABLE 105 Dry powder containing fish oil (50% DHA/EPA) and TPGS wt % ofIngredient composition KHCO₃ 7.73 (stabilizer) Green tea extract (40%EGCG) 18.96 (stabilizer) Vitamin C 4.64 (stabilizer) SALADIZER ®emulsifier 0.15 (emulsion stabilizer) SFAE 14.53 (co-surfactant) Saponin1.41 (co-emulsifier) Green tea flavor (flavor) Pre-emulsion concentrate52.58 containing fish oil (50% DHA/EPA) and TPGS (Table 99 above) Totals100.00

TABLE 106 Dry powder containing astaxanthin (10% astaxanthin) and TPGSwt % of Ingredient composition KHCO₃ 10.70 (stabilizer) Vitamin C 4.64(stabilizer) SALADIZER ® emulsifier 0.15 (emulsion stabilizer) SFAE19.17 (co-surfactant) Saponin 0.56 (co-emulsifier) Highly branchedcyclic dextrin (HBCD) 26.14 (binder/carrier) Pre-emulsion concentrate38.64 containing astaxanthin and TPGS (Table 100 above) Totals 100.00

TABLE 107 Dry powder containing dihydrocapsiate and TPGS wt % ofIngredient composition SALADIZER ® emulsifier 0.15 (emulsion stabilizer)SFAE 19.17 (co-surfactant) Saponin 1.41 (co-emulsifier) Maltodextrin29.92 (binder/carrier) Citric acid 10.70 (pH adjuster) Pre-emulsionconcentrate 38.65 containing dihydrocapsiate and TPGS (Table 101 above)Totals 100.00

TABLE 108 Dry powder containing MCT oil (98% MCT), vitamin K2 (97%MK-7), benzyl alcohol, and TPGS wt % of Ingredient compositionSALADIZER ® emulsifier 0.15 (emulsion stabilizer) SFAE 10.36(co-surfactant) Highly branched cyclic dextrin (HBCD) 39.10(binder/carrier) Sorbitol 19.32 (sweetener) Pre-emulsion concentrate31.07 containing MCT oil, vitamin K2 (MK-7), benzyl alcohol and TPGS(Table 102 above) Totals 100.00

The dry powders depicted above in Tables 104-108 that contained thepre-emulsion concentrates described in Tables 93-97, above, containedbetween 11.18% and 51.22% by weight non-polar ingredient(s), as shown inTable 109, below.

TABLE 109 Amount of non-polar ingredient in dry powders wt % ofpre-emulsion wt % of non-polar concentrate in dry ingredient in dryNon-polar ingredient powder powder Fish oil 31.87 31.05 (Table 104above) Fish oil 52.58 51.22 (Table 105 above) Astaxanthin 38.64 30.91(Table 106 above) Dihydrocapsiate 38.65 14.34 (Table 107 above) MCToil/vitamin K2 (MK-7) 31.07 11.18 (Table 108 above)

Example 10 Preparation of a Dry Powder by Instantization

A. Preparation of the Pre-Emulsion Concentrate

A pre-emulsion concentrate was prepared according to the methoddescribed above in Example 2 using the ingredients detailed in Table110, below. The pre-emulsion concentrate contained TPGS, prepared asdescribed in Example 1, above, and a total of 93.42% by weight (of theconcentrate) non-polar ingredients that included a coenzyme Q10 (coQ10)compound that contains 99% ubidicarenone (ubiquinone) sold under thename Kaneka Q10™ (USP Ubidicarenone; Kaneka Nutrients, L.P., Pasadena,Tex.); astaxanthin (an oil containing 10% astaxanthin sold as AstaPure®by Alga Technologies, Hevel Eilot, Israel); pyrroloquinoline quinone(PQQ) (sold by Nascent Health Sciences, Allentown, N.J.); and a mediumchain triglyceride (MCT) that contains 95% MCT (sold as Captex® 300 byAbitec, Columbus, Ohio).

The pre-emulsion concentrate set forth in Table 110, below, was madeusing a bench-top process according to the provided methods (see Example2). The pre-emulsion concentrate can alternatively be made by scaling upthe bench-top process, using a scaled-up manufacturing process of theprovided methods, for example, to make larger batch sizes of thepre-emulsion concentrate.

TABLE 110 Pre-emulsion concentrate containing coQ10, astaxanthin, PQQ,MCT, and TPGS wt % of Ingredient composition CoQ10 (99% ubiquinone) 1.21Astaxanthin (10% astaxanthin) 4.00 PQQ (99% PQQ) 0.70 MCT (95% MCT)87.51 TPGS 6.58 Total 100.00

B. Preparation of the Pre-Spray Emulsion

The pre-emulsion concentrate described above and shown in Table 110 wasused in the preparation of a pre-spray emulsion. The pre-spray emulsionwas prepared by combining the pre-emulsion concentrate that contained93.42% of the non-polar ingredients coQ10, astaxanthin, PQQ and MCT,described in Table 110, above, with the ingredients detailed in Table111, below, according to the general procedure described above inExample 3. The resulting pre-spray emulsion thus contained 16.75% byweight pre-emulsion concentrate containing 93.42% of the non-polaringredients coQ10, astaxanthin, PQQ and MCT (i.e., the resultingpre-spray emulsion contained a total of 15.65% by weight non-polaringredient).

The ingredients in the pre-spray emulsion included the pre-emulsionconcentrate prepared as described above (see Table 110); a surfactant, asucrose fatty acid ester (SFAE; sold under the trade name DK Ester®,produced by Dai-Ichi Kogyo Seiyaku Co., Ltd of Japan); an emulsionstabilizer that was a blend of xanthan gum, guar gum and sodiumalginate, sold under the product name SALADIZER®, available from TICGums, Inc. (Belcamp, Md.); the binders maltodextrin (sold by ArcherDaniels Midland Company, Decatur, Ill.) and a highly branched cyclicdextrin (HBCD) (sold as Cluster Dextrin® by Glico Nutrition, Japan);stabilizers, including potassium bicarbonate and green tea extract thatcontained 60% epigallocatechin gallate (EGCG) (Guilin Layn NaturalIngredients, Corp., Guilin, China); sweeteners, including pure canesugar; additional ingredients, including citicholine (sold as Cognizin®Citicholine by Kyowa Hakko USA, New York, N.Y.) and caffeine (sold asCaffeine Anhydrous powder (white, crystalline powder), by PacificRainbow International, Inc., City of Industry, Calif.); silicon dioxide;and a polar solvent, water, which was purified city water, purified asdescribed above (see Example 3). Before adding to the appropriate phase,as described above, the correct amount of each ingredient (as indicatedin Table 111) was weighed out using either a Sartorius Basic AnalyticalScale (Model BA110S), an OHAUS Scale (Model CS2000) or a Toledo Scale(Model GD13x/USA). Liquid ingredients were weighed in containers, whiledry ingredients were weighed in bags.

Table 111, below, indicates the amount (g) of each ingredient per batchof the pre-spray emulsion, the phase each ingredient was added, and thepercentage by weight (wt %) of each ingredient.

TABLE 111 Pre-spray emulsion containing coQ10, astaxanthin, PQQ, MCT,and TPGS wt % of Ingredient g/batch Phase composition Water 287.5 Water57.50 (polar solvent) KHCO₃ 14.67 Water 2.93 (stabilizer) Green teaextract (60% EGCG) 13.33 Water 2.67 (stabilizer) SALADIZER ® emulsifier0.33 Water 0.07 (emulsion stabilizer) SFAE 6.67 Water 1.33(co-surfactant) Highly branched cyclic dextrin (HBCD) 14.23 Water 2.85(binder/carrier) Maltodextrin 21.67 Water 4.33 (binder/carrier) Silicondioxide 2.17 Water 0.43 (anticaking agent) Citicholine 12.50 Water 2.50(active ingredient) Caffeine 4.73 Water 0.95 (active ingredient) Canesugar 38.45 Water 7.69 (sweetener) Pre-emulsion concentrate 83.75 Oil16.75 containing coQ10, astaxanthin, PQQ, MCT and TPGS (Table 110above)Totals 500.00 100.000

C. Preparation of the Dry Powder

The pre-spray emulsion described above and indicated in Table 111 thenwas spray dried into an initial dry powder according to the proceduredetailed in Example 4. The addition of extra water (i.e., evaporationwater) to the pre-spray emulsion was required as a processing aid tomake the emulsion thinner and able to pass through the dryer pump moreeasily. The extra water was added to the pre-spray emulsion at 35° C.and was evaporated during the spray dry process, along with the rest ofthe water in the pre-spray emulsion.

The initial dry powder contained 39.41% of the pre-emulsion concentratecontaining 93.42% coQ10, astaxanthin, PQQ, and MCT (i.e., 36.82%non-polar ingredients). Table 112, below, indicates the percentage byweight (wt %) of each ingredient per batch of the initial dry powderafter spray drying the pre-spray emulsion.

TABLE 112 Initial dry powder containing coQ10, astaxanthin, PQQ, MCT,and TPGS wt % of Ingredient composition KHCO₃ 6.90 (stabilizer) Greentea extract (60% EGCG) 6.27 (stabilizer) SALADIZER ® emulsifier 0.16(emulsion stabilizer) SFAE 3.14 (co-surfactant) Highly branched cyclicdextrin (HBCD) 6.70 (binder/carrier) Maltodextrin 10.20 (binder/carrier)Silicon dioxide 1.02 (anticaking agent) Citicholine 5.88 (activeingredient) Caffeine 2.23 (active ingredient) Cane sugar 18.09(sweetener) Pre-emulsion concentrate 39.41 containing coQ10,astaxanthin, PQQ, MCT and TPGS (Table 110 above) Total 100.00The initial dry powder thus contained 36.82% of the non-polaringredients coQ10, astaxanthin, PQQ, and MCT.

The initial dry powder was then instantized to form a final dry powder.The initial dry powder was instantized by first rewetting the surface ofthe individual particles (by adding water), allowing the particles tocome into contact and stick together, and then drying to remove thewater, causing individual particles to stick together as agglomerates.Agglomerization was facilitated by addition of sugars and/or sugaralcohols. Silicon dioxide and maltodextrin were also added to facilitatethe drying process. Table 113, below, indicates the amount (g) of eachingredient per batch and the percentage by weight (wt %) of eachingredient of the rewetted powder.

TABLE 113 Rewetted powder containing the initial dry powder containingcoQ10, astaxanthin, PQQ, MCT, and TPGS wt % of Ingredient compositionWater 35.00 Pure cane sugar 9.42 Silicon dioxide 0.66 (anticaking agent)Maltodextrin 9.42 (binder/carrier) Initial dry powder containingnon-polar ingredient coQ10, 45.50 astaxanthin, PQQ, MCT, and TPGS (Table110 above) Total 100.00

The rewetted powder depicted above in Table 113 then was dried byfluidized bed drying to form the final instantized dry powder. Theresulting final dry powder was a more granular product with improvedwettability of the powder (i.e., the powder gets wet quickly anddisperses in water quickly without any lumping). Table 114, below,indicates the percentage by weight (wt %) of each ingredient per batchof the final dry powder after instantization of the rewetted powder.

TABLE 114 Rewetted powder containing the initial dry powder containingcoQ10, astaxanthin, PQQ, MCT, and TPGS wt % of Ingredient compositionPure cane sugar 14.49 Silicon dioxide 1.01 (anticaking agent)Maltodextrin 14.49 (binder/carrier) Initial dry powder containingnon-polar ingredient coQ10, 70.00 astaxanthin, PQQ, MCT, and TPGS (Table110 above) Total 100.00The final dry powder, after instantization, thus contained 25.77% of thenon-polar ingredients coQ10, astaxanthin, PQQ, and MCT and was a moregranular powder than the initial dry powder.

Example 11 Preparation of Non-Aqueous Pre-Gel Concentrates ContainingTPGS, Benzyl Alcohol or Benzyl Alcohol and d-Limonene and Non-PolarIngredients

Non-aqueous pre-gel concentrates were prepared according to theprocedure described below and containing the ingredients listed below.The non-aqueous pre-gel concentrates contained α-tocopheryl polyethyleneglycol succinate (TPGS), benzyl alcohol or benzyl alcohol andd-limonene, and one or more non-polar ingredients. After formation ofthe non-aqueous pre-gel concentrates, the compositions were encapsulatedin a collagen-containing shell to form a soft gel.

A. Ingredients

The non-aqueous pre-gel concentrates contained between 26.96% and 34.6%TPGS and between 7.49% and 15.42% benzyl alcohol or benzyl alcohol andd-limonene. The remainder of the concentrates, between 54.8% and 65.55%,contained one or more non-polar ingredients.

Ingredients in the non-aqueous pre-gel concentrates included:

TPGS, a surfactant, that contained a high amount of the dimer form(e.g., 85%-90%) and a low amount of the monomer form (e.g., 10%-15%),such as the TPGS described in Example 1, above. See also, U.S. patentapplication Ser. No. 14/207,310 and International PCT Application No.PCT/US14/25006, now published as US-2014-0271593-A1 and WO 2014/151109,respectively;

one or more non-aqueous solvents, including benzyl alcohol (SigmaAldrich, St. Louis, Mo.) and d-limonene (99% GRAS-certified; FloridaChemical, Winter Haven, Fla.); and

one or more non-polar ingredients that are or contain non-polarcompounds, including: vitamins, including vitamin E oil (such as thevitamin E oil sold under the name Novatol™ 5-67 (D-alpha-tocopherol) byADM Natural Health and Nutrition, Decatur, Ill.), vitamin D3 (1.0million IU/gram; DSM, Parsippany, N.J.) and vitamin K2 (as MK-7;NattoPharma®, Metuchen, N.J.); a borage oil compound that contains notless than (NLT) 22% of the non-polar compound C18:3 gamma-linolenic acid(GLA) (such as the borage oil sold by Sanmark Limited, Dalian, LiaoningProvince, China); alpha-lipoic acid (such as sold by NutriChem ResourcesCompany, Walnut, Calif., and Zhejiang Medicines & Health Products Import& Export Co., Ltd., Hangzhou, China); ubiquinol (Kaneka Ubiquinol®, soldby Kaneka Nutrients, Pasadena, Tex.); pyrroloquinoline quinone (PQQ;such as PureQQ, sold by Nascent Health Science, Allentown, N.J.);carotenoid-containing compounds, including astaxanthin (such asAstraREAL®, sold by Fuji Health Science, Burlington, N.J.; AstaPure®,sold by Alga Technologies, Hevel Eilot, Israel; BioAstin®, sold byCyanotech, Kailua-Kona, Hi.); fatty acids and fatty acid derivatives,including an oleic acid compound that contains 70% oleic acid (MCChemicals, Inc., New Paltz, N.Y.) and cetyl myristoleate, an esterifiedderivative of myristoleic acid (sold as Myristin®, EHP Products, Inc.,Mt. Pleasant, S.C.); a phospholipid, lecithin (phosphatidylcholine; suchas Lecithin Ultralec® P, ADM Natural Health and Nutrition, Decatur,Ill.; and Phospholipon®, a lecithin fraction with approximately 95%phosphatidylcholine, sold by Lipoid, Steinhausen, Switzerland, andAmerican Lecithin Company, Oxford, Conn.); a turmeric/curcumincomposition that contains 95% curcumin (sold by Siddharth International,Mumbai, India); Perluxan™, a hops (Humulus lupulus L.) extract thatcontains a minimum of 30% alpha acids (including humulone, co-humulone,adhumulone, iso-cohumulone and iso-adhumulone) and 10% beta acids(lupulone and colupulone) (sold by Pharmachem Laboratories, Kearny,N.J.); and ApresFLEX®, a Boswellia extract that containsacetyl-11-keto-β-boswellic acid (AKBA; sold by PLT Health Solutions,Morristown, N.J.).

B. Preparation of the Non-Aqueous Pre-Gel Concentrates

The non-aqueous pre-gel concentrates were made by a bench-top processaccording to the methods described below. Alternatively, theconcentrates can be prepared by scaling up the bench-top process to makelarger batch sizes of the non-aqueous pre-gel concentrates.

For each non-aqueous pre-gel concentrate, the appropriate amount of eachingredient was weighed using a Toledo Scale (Model GD13x/USA), SartoriusBasic Analytical Scale (Model BA110S), an OHAUS Scale (Model CS2000) ora CTS 6000 Scale (Model CTS-6000). Selection of the scale was dependenton the weight of each ingredient being weighed.

The appropriate amounts of TPGS, benzyl alcohol, and d-limonene (whenindicated) were added to a vessel (e.g., a Pyrex® beaker) and heated to60° C. using a Thermolyne hot plate while mixing with a standard mixer(IKA® Model No. RE-16 S1, an overhead mixer (laboratory stirrer)compatible with the bench-top process). Once the initial ingredientsdissolved and formed a homogeneous mixture, the non-polar ingredientswere added. The ingredients then were homogenized by placing areversible homogenizer (Arde Barinco, Inc., Model No. CJ-4E) in thevessel (beaker) and turning it on at 850-1200 rpm. Mixing with thehomogenizer continued while maintaining the temperature at 60° C. usingthe hot plate until the mixture became homogenous. During mixing, thebaffle plate on the homogenizer was adjusted to achieve and maintain anemulsion, for example, by moving the baffle plate further into and/orout of the ingredient mixture.

The composition then was filtered, using a 100-400 micron filter andthen packaged (transferred) by filling into one or more storagecontainers, such as plastic bottles or 5 gallon pails, where it wascooled to room temperature (about 25° C.). Alternatively, the mixturecan be packaged into a bag-in-a-box type storage container. Each of thenon-aqueous compositions was a liquid at room temperature.

C. Preparation of Soft-Gel Capsules

Soft gel capsules were prepared by a service provider (Captek SoftgelInternational, Cerritos, Calif.) from a gelatin or other suitablematerial using standard methods. The outer capsule is formed, forexample, using a polar emulsion and gelatin or other known gelreplacement, at an appropriate ratio to form the gel capsule. Thecapsule is of a size to encompass a dosage amount for direct oralconsumption and is filled with an appropriate selected dosage of acomposition as described above.

Example 12 Exemplary Pre-Gel Concentrates

Exemplary pre-gel concentrates are provided below. These were introducedinto soft gel capsules to form soft gel compositions. Tables 115-118,below, set forth the ingredients in the non-aqueous pre-gelconcentrates, the grams of each ingredient per batch, the amount (mg) ofeach ingredient per 0.5 mL serving, and the percentage by weight (wt %)of each ingredient by weight of the composition. The non-aqueouscompositions were prepared according to the provided methods using abench-top process, described above. Each of the non-aqueous compositionswas a liquid at room temperature.

TABLE 115 Non-aqueous pre-gel concentrate containing TPGS, benzylalcohol, and 56.19% non-polar ingredients mg/0.5 mL wt % (of Ingredientg/batch serving composition) TPGS 6388.13 340.7 28.39 Benzyl alcohol3468.75 185 15.42 Vitamin E oil (Novatol ™ 5-67) 768.75 41 3.42 Borageoil (NLT 22% GLA) 9375.00 500 41.67 Alpha-lipoic acid 1031.25 55 4.58Ubiquinol 281.25 15 1.25 PQQ 112.50 6 0.50 Astaxanthin 1031.25 55 4.58Vitamin K2 (180 mcg MK-7) 3.75 0.2 0.017 Vitamin D3 (1 million IU/g)39.38 2.1 0.175 Totals 22500.00 1200 100.00

TABLE 116 Non-aqueous pre-gel concentrate containing TPGS, benzylalcohol, and 54.8% non-polar ingredients mg/0.5 mL wt % (of Ingredientg/batch serving composition) TPGS 51.90 173 34.6 Benzyl alcohol 15.90 5310.6 Oleic acid 30.00 100 20.0 Vitamin E oil (Novatol ™ 5-67) 10.20 346.8 Astaxanthin 42.00 140 28.0 Totals 150.00 500 100.00

TABLE 117 Non-aqueous pre-gel concentrate containing TPGS, benzylalcohol, and 61.2% non-polar ingredients mg/0.5 mL wt % (of Ingredientg/batch serving composition) TPGS 42.37 564.999 28.25 Benzyl alcohol15.83 211 10.55 Oleic acid 38.63 515 25.75 Cetyl myristoleate 45.30 60430.20 (Myristin ®) ApresFLEX ® 7.88 105 5.25 (Boswellia extract) VitaminD3 0.000054 0.00072 0.000036 (1 million IU/g) Totals 150.00 2000 100.00

TABLE 118 Non-aqueous pre-gel concentrate containing TPGS, benzylalcohol and d-limonene, and 65.55% non-polar ingredients mg/0.5 mL wt %(of Ingredient g/batch serving composition) TPGS 26.96 785 26.96 Benzylalcohol 2.85 83 2.85 d-Limonene 4.64 135 4.64 Lecithin 30.05 875 30.05Turmeric/curcumin 2.06 60 2.06 (95% curcumin) Cetyl myristoleate 20.74604 20.74 (Myristin ®) ApresFLEX ® 3.61 105 3.61 (Boswellia extract)Perluxan ™ 9.10 265 9.10 (hops extract) Vitamin D3 0.000025 0.000720.000025 (1 million IU/g) Totals 100.00 2912 100.00

Example 13 Preparation of Non-Aqueous Pre-Gel Concentrates and Soft GelCapsules Containing TPGS and Non-Polar Ingredients

A. Preparation of Non-Aqueous Pre-Gel Concentrates

Non-aqueous pre-gel concentrates were prepared according to theprocedure described above in Example 11. The non-aqueous pre-gelconcentrates contained TPGS and one or more non-polar ingredients. Someof the concentrates also contained benzyl alcohol. After formation ofthe non-aqueous pre-gel concentrates, the compositions were encapsulatedin a collagen-containing shell to form a soft gel.

The non-aqueous pre-gel concentrates contained between 9% and 31.78%TPGS up to 91% of one or more non-polar ingredients. Ingredients in thenon-aqueous pre-gel concentrates included:

TPGS, a surfactant, that contained a high amount of the dimer form(e.g., 85%-90%) and low amount of the monomer form (e.g., 10%-15%), suchas the TPGS prepared according Example 1;

non-aqueous solvents, including benzyl alcohol (Sigma Aldrich, St.Louis, Mo.); and

one or more non-polar ingredients that are or contain non-polarcompounds, including: almond oil; an oleic acid compound that contains70% oleic acid (MC Chemicals, Inc., New Paltz, N.Y.); a cannabidiol oilthat contains 30% cannabidiol; coenzyme Q10-containing compounds,including ubiquinol (Kaneka Ubiquinol®, sold by Kaneka Nutrients,Pasadena, Tex.) and a ubiquinone compound that contains greater than 98%ubidicarenone (ubiquinone), sold under the name Kaneka Q10™ (USPUbidicarenone; Kaneka Nutrients, L.P., Pasadena, Tex.); natural flavors;pyrroloquinoline quinone (PQQ; such as PureQQ, sold by Nascent HealthScience, Allentown, N.J.); an algal oil that contains 35% of thenon-polar compound DHA and contains 350 mg DHA/g oil (life'sDHA™S35-O300, sold by DSM Nutritional Products Inc., Kaiseraugst,Switzerland); and a medium chain triglyceride (MCT) oil that contains98% MCT (sold by Abitec, Janesville, Wis. and Stepan Lipid Nutrition,Maywood, N.J.).

Tables 119-123, below, set forth the ingredients in the non-aqueouspre-gel concentrates, the grams of each ingredient per batch, the amount(mg) of each ingredient per 0.5 mL serving, and the percentage by weight(wt %) of each ingredient by weight of the composition. The non-aqueouspre-gel concentrates were made by a bench-top process according to themethods described above in Example 11. Alternatively, the concentratescan be prepared by scaling up the bench-top process to make larger batchsizes of the non-aqueous pre-gel concentrates. Each of the non-aqueouspre-gel compositions was a liquid at room temperature.

TABLE 119 Non-aqueous pre-gel concentrate containing TPGS and 80%non-polar ingredients mg/0.5 mL wt % (of Ingredient g/batch servingcomposition) TPGS 30.00 30.00 20.00 Almond oil 10.00 10.00 6.67 Oleicacid 84.00 84.00 56.00 Cannabidiol oil 26.00 26.00 17.33 Totals 150.00150.00 100.00

TABLE 120 Non-aqueous pre-gel concentrate containing TPGS and 91%non-polar ingredients mg/0.5 mL wt % (of Ingredient g/batch servingcomposition) TPGS 90.00 216.00 9.00 Natural flavor 62.92 6.29 6.29 Algaloil (35% DHA) 847.08 84.71 84.71 Totals 1000.00 2400.00 100.00

TABLE 121 Non-aqueous pre-gel concentrate containing TPGS and 89.25%non-polar ingredients mg/0.5 mL wt % (of Ingredient g/batch servingcomposition) TPGS 3332.50 215 10.75 MCT oil 27667.50 1785 89.25 Totals31000.00 2000.00 100.00

TABLE 122 Non-aqueous pre-gel concentrate containing TPGS, benzylalcohol and 63.03% non-polar ingredients mg/0.5 mL wt % (of Ingredientg/batch serving composition) TPGS 276.66 153.70 15.37 Benzyl alcohol388.80 216.00 21.60 Oleic acid 756.54 420.30 42.03 Ubiquinone 378.00210.00 21.00 Totals 1800.00 1000.00 100.00

TABLE 123 Non-aqueous pre-gel concentrate containing TPGS, benzylalcohol and 41.05% non-polar ingredients mg/0.5 mL wt % (of Ingredientg/batch serving composition) TPGS 95.35 190.70 31.78 Benzyl alcohol81.50 163.00 27.17 Oleic acid 84.65 169.30 28.22 PQQ 12.00 24.00 4.00Ubiquinol 26.50 53.00 8.83 Totals 300.00 600.00 100.00

B. Preparation of Soft-Gel Capsules

Soft gel capsules containing each of the pre-gel concentrates set forthin Tables 119-123, above, were prepared by Captek Softgel International(Cerritos, Calif.) from a gelatin or other suitable material usingstandard methods. The outer capsule was formed using a polar emulsionand gelatin or other known gel replacement, at an appropriate ratio toform the gel capsule. The capsule was of a size to encompass a dosageamount for direct oral consumption and was filled with an appropriateselected dosage of a composition as described above.

Since modifications will be apparent to those of skill in this art, itis intended that this invention be limited only by the scope of theappended claims.

The invention claimed is:
 1. A non-aqueous pre-gel composition,comprising: a water-soluble vitamin E derivative mixture present in anamount from 1% to 99%, inclusive, by weight, of the composition,wherein: the water-soluble vitamin E derivative is a polyalkylene glycolderivative of vitamin E; and the water-soluble vitamin E derivativemixture comprises at least 13 wt % water-soluble vitamin E derivativedimer and up to 87 wt % water-soluble vitamin E derivative monomer; anon-polar compound or mixtures thereof other than the water-solublevitamin E derivative mixture; and an ingestible non-aqueous solvent thatis insoluble in water or that has low water solubility.
 2. Thecomposition of claim 1, wherein the water-soluble vitamin E derivativeis a polyethylene glycol (PEG) derivative of vitamin E.
 3. Thecomposition of claim 2, wherein the PEG derivative of vitamin E istocopheryl polyethylene glycol succinate (TPGS).
 4. The composition ofclaim 3, wherein the TPGS is TPGS-1000.
 5. The composition of claim 3,wherein the water-soluble vitamin E derivative mixture contains 29%-69%,inclusive, by weight, of dimer; and contains less than 70 wt % of thevitamin E derivative monomer.
 6. The composition of claim 4, wherein themonomer comprises between 35% and 65%, inclusive, by weight, of thewater-soluble vitamin E derivative mixture and the dimer comprisesbetween 25% and 65%, by weight, of the water-soluble vitamin Ederivative mixture.
 7. The composition of claim 1, wherein thenon-aqueous solvent is selected from aromatic compounds, haloalkanes,ethers, esters, ketones, organic solvents of natural origin, alkylketones, tetrahydrofuran, cyclic alkyl amides, decyl methyl sulfoxide,oleic acid, aromatic amines, natural oils, or acyl glycerols.
 8. Thecomposition of claim 7, wherein the non-aqueous solvent is selected fromd-limonene, benzyl alcohol, benzyl benzoate, terpenes, alpha-pinene,beta-pinene, myrcene, linalol, citronellol, geraniol, menthol, citral,citronellal, N-methyl pyrrolidone (NMP), alkylene glycols, dimethylsulfoxide, dimethyl acetamide, 2-pyrrolidone, C2-C6 alkanols,2-ethoxyethanol, 2-ethoxyethyl acetate, methyl acetate, ethyl acetate,ethylene glycol diethyl ether, ethylene glycol dimethyl ether,(S)-(−)-ethyl lactate, acetone, glycerol, methyl ethyl ketone, dimethylsulfone, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleicacid, N,N-diethyl-m-toluamide, 1-dodecylazacycloheptan-2-one, olive oilsor fatty acids.
 9. The composition of claim 1, wherein the amount of thenon-aqueous solvent is at least 7%, up to and including 30%, by weight,of the composition.
 10. The composition of claim 3, comprising: anon-aqueous solvent in an amount between 2% and 40%, or greater than 5%,up to 50%, inclusive, by weight, of the composition; the polyethyleneglycol (PEG) derivative of vitamin E mixture in an amount between 5% and50%, inclusive, by weight, of the composition; and a non-polaringredient, other than the PEG derivative of vitamin E, in an amountbetween 10% and 90%, inclusive, by weight, of the composition.
 11. Thecomposition of claim 1, wherein the non-aqueous solvent is an alcohol,an ester derivative of an alcohol, a hydrocarbon, or mixtures thereof.12. The composition of claim 11, wherein the non-aqueous solvent isselected from among benzyl alcohol, benzyl benzoate, d-limonene ormixtures thereof.
 13. The composition of claim 1, wherein the non-polaringredient is or contains a non-polar compound selected frompolyunsaturated fatty acids (PUFAs), non-essential fatty acids,phospholipids, coenzyme Q compounds, flavonoids, carotenoids,micronutrients, Boswellia extracts, alkaloids, hops-containingcompounds, antioxidants, or mixtures thereof.
 14. The composition ofclaim 1, wherein the non-polar compound is present in an amount of frombetween 40% and 90%, by weight, of the composition.
 15. A capsulecomposition, comprising a non-aqueous pre-gel composition of claim 1 ina shell or coating.
 16. A capsule composition, comprising a non-aqueouspre-gel composition of claim 5 in a shell or coating.
 17. The capsulecomposition of claim 16, wherein the non-aqueous solvent is an alcohol,an ester derivative of an alcohol, a hydrocarbon, or mixtures thereof.18. The capsule composition of claim 17, wherein the non-aqueous solventis benzyl alcohol, benzyl benzoate, d-limonene, and or mixtures thereof.19. The capsule composition of claim 15, wherein the shell or coating isa gelatin or gelatin substitute shell or coating.
 20. A method of makingthe pre-gel composition of claim 1, comprising: a) mixing and heatingingredients in a vessel; b) homogenizing the ingredients; and c) coolingthe mixed ingredients, whereby the mixed ingredients become a pre-gelliquid composition.
 21. The method of claim 20, further comprisingintroducing the pre-gel composition into a soft gel shell or capsule.22. A method of providing a non-polar compound to a subject, comprisingadministering a capsule of claim 15 to the subject.